Adjuvant RT Remains the Standard of Care at This Time
Ductal carcinoma in situ (DCIS) was first recognized in the 1970s. Within a decade, it became appreciated as a significant clinical entity due to the widespread implementation of breast cancer screening programs. More than 60,000 cases of DCIS are diagnosed in the United States annually, accounting for approximately one-quarter of new breast cancer diagnoses each year. DCIS is, in fact, a premalignant lesion, but appropriate management is critical. When untreated, it can progress to invasive cancer and ultimately death; in 2005, retrospective series of cases managed without active treatment demonstrated a breast cancer mortality rate of approximately 10% to 20% with small numbers of cases. More recent data demonstrate a rate of 3.3% with treatment of DCIS. This difference is largely attributed to the approximately 10% risk of invasive ipsilateral breast tumor recurrence (IBTR) observed even in the treated population (without radiation therapy [RT]), and the associated increase in breast cancer mortality.[4-7] Current management of DCIS is driven by multiple landmark trials showing that lumpectomy should be coupled with RT to reduce rates of local recurrence (particularly invasive recurrence) and later with anti-estrogen therapy to maximize local control.[8-12] However, the clinical and genomic landscape of DCIS is now better understood, and treatment can be risk stratified to limit not only the intensity and toxicities of treatment, but also its physical, emotional, and financial consequences.
The fundamental role of RT in the treatment of DCIS was established by four landmark trials randomizing post-lumpectomy patients to adjuvant RT vs no RT: the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial, SweDCIS, the European Organisation for Research and Treatment of Cancer 10853 trial, and the UK Coordinating Committee on Cancer Research trial. Each study demonstrated that the addition of RT reduced the risk of any IBTR by approximately 50%.[8-11] All four studies showed a statistically significant reduction in invasive recurrences with RT, a notable finding, given that recurrences are associated with increased breast cancer mortality.[4,12] That said, none of these trials nor a meta-analysis of these studies demonstrated an overall survival (OS) benefit from the use of RT.
Because of the observed lack of an OS benefit with RT, omission of RT in “low-risk” DCIS has been investigated. The Eastern Cooperative Oncology Group (ECOG) E5194 trial prospectively followed more than 700 women with margins ≥ 3 mm and either low-/intermediate-grade DCIS measuring ≤ 2.5 cm or high-grade DCIS measuring ≤ 1.0 cm. At 12 years, the overall rate of IBTR was 14% in women with grade 1/2 disease but was 25% in those with grade 3 disease, with no plateau in recurrences noted for either group—an unacceptably high rate in either cohort. The Dana-Farber experience provides additional data on observation after surgical resection in women with grade 1/2 disease < 2.5 cm mammographically and wide margins (≥ 1 cm). Even in this low-risk population, the 8-year local recurrence rate was > 13%, with one-third of patients having an invasive recurrence.
The Radiation Therapy Oncology Group (RTOG) 9804 trial also evaluated the omission of RT in DCIS; however, in contrast to the single-arm approach used in the ECOG and Dana-Farber studies, low-risk women were randomized to RT vs no RT following breast-conserving surgery (BCS). Low-risk criteria were slightly different from those used in the ECOG study and included grade 1/2 disease, extent of DCIS ≤ 2.5 cm, and margins ≥ 3 mm. This study closed due to poor accrual. Nonetheless, its findings are notable: even in this low-risk population, the reduction in the IBTR rate with the use of RT was significant (from a 7% IBTR rate without RT to 1% with RT at 7-year follow-up; P < .001). In addition, RT was well tolerated: acute grade 3 toxicity was similar in both arms (about 4%), and late grade 3 toxicity was < 1% in the RT arm. RTOG 9804 echoes the ECOG study in that the recurrence risk was approximately 1% per year in low-risk patients who omitted RT, with neither study clearly demonstrating factors predictive of invasive recurrences. Notably, these studies did not require routine use of anti-estrogen therapy; rates of treatment with anti-estrogen agents ranged from 0% in the Dana-Farber trial, to 30% in the ECOG study, to 62% in both arms of RTOG 9804. The benefit of adjuvant RT would likely have been less substantial if all women had, indeed, received anti-estrogen therapy; however, even in the closely monitored setting of an active clinical trial, high compliance rates are difficult to achieve, as demonstrated by the 70% compliance rate seen in NSABP B-35, a trial specifically evaluating endocrine therapy.
While local recurrence is certainly clinically and psychologically taxing, some argue that since no randomized trial has shown an OS benefit with adjuvant RT, post-lumpectomy RT is not needed for many patients with DCIS. Instead, the concept would be that clinicians should initiate close surveillance as part of follow-up care, and salvage therapy when indicated. However, the failure to demonstrate improved survival with RT does not mean that it does not exist; it may be that because the breast cancer–specific mortality associated with DCIS is low (approximately 3% at 10 years), the sample size needed to detect a statistically significant improvement in OS is prohibitively large. This is where population-based data become helpful, not only because large databases can provide information about national practices, but also because they include enough patients to enable clinicians to evaluate treatment approaches of potential significance with respect to a disease site for which outcomes are generally very favorable. An analysis of Surveillance, Epidemiology, and End Results data by Sagara et al provides some insight into the treatment and outcomes associated with DCIS across the United States. The authors evaluated more than 30,000 patients, detecting a low breast cancer mortality rate of 2%, but an improvement was noted with the addition of RT (1.8% with RT vs 2.1% without RT). Despite this improvement, approximately 40% of patients with DCIS never received RT. Notably, RT improved survival in patients with three important risk factors: high nuclear grade tumors, younger age (< 60 years), and larger tumor size; these are findings that individual randomized controlled trials have not been able to demonstrate. Additionally, the study specifically evaluated the utility of the patient prognostic score initially developed by Smith et al in 2006, which incorporates grade, age, size, and comedo histology. Sagara’s study showed that patients with prognostic scores of 4 or 5 (with 5 being the highest score) had a nearly 70% reduction in breast cancer mortality with the use of RT, with an absolute difference of 4% in those with scores of 5 (P = .03). This result is comparable to findings from the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of invasive cancers, which is often quoted as evidence of a mortality benefit from use of RT with BCS in early-stage invasive breast cancer.
Given the changing landscape of DCIS treatment paradigms, the use of prognostic indices may help to delineate which patients will most likely benefit from RT. The aforementioned Smith prognostic score is an effective tool for making this assessment; another scoring method, the Van Nuys Prognostic Index, has been neither widely used nor consistently externally validated. Analysis of tumor genetics represents a novel strategy to risk-stratify DCIS patients into low- , intermediate- , and high-risk groups. A study evaluating a subset of patients from the aforementioned ECOG trial found that rates of invasive recurrence were 4%, 12%, and 19% for low- , intermediate- , and high-risk patients, respectively. More recently, this genetic assay was validated in a larger patient cohort, and again showed that the Oncotype DX DCIS Score was predictive of local recurrence; however, concerns remain regarding the high rate of recurrences in the low-risk group (13% at 10 years; 5% invasive) and the cost effectiveness of such an approach.[23,24] There are limited data to support the use of currently available prognostic tools or tumor genetics to define which patients require adjuvant RT. However, in some cases these tools may help to individualize the shared decision that patients and clinicians ultimately make regarding the use of RT.
One common concern regarding adjuvant RT for DCIS is the duration of treatment. However, randomized data in the invasive setting have demonstrated equivalent clinical outcomes and toxicity with hypofractionated whole-breast irradiation (delivered over a period of 3 weeks) vs standard radiation (of 5 weeks’ duration).[25,26] Data on the use of hypofractionation for DCIS are derived from single-institution studies as well as regional analyses from Canada.[27,28] Additionally, the use of accelerated partial-breast irradiation allows completion of adjuvant RT in ≤ 1 week, without compromising local control, and is a standard-of-care option in appropriately selected women with DCIS. In selected patients, hypofractionation and accelerated partial-breast irradiation are attractive options, since they reduce the treatment duration by ≥ 50% (increasing patients’ ability to receive and complete adjuvant RT) and are associated with favorable oncologic and cosmetic outcomes. At this time, guidelines from the American College of Radiology and the National Comprehensive Cancer Network support routine use of adjuvant RT in all patients with DCIS, since no subgroup who can safely forgo RT has been clearly identified—with the caveat that older patients and/or those with significant comorbidities may be considered for lumpectomy alone. In the context of these guidelines, several factors provide a good foundation for treatment decision making: patient age; comorbidities; and the potential for locoregional recurrence, based on factors such as tumor grade, margins, and receptor status. It is also important to bear in mind that patients with grade 3 disease or positive margins are at particularly high risk of recurrence. Current studies, including those evaluating nonoperative management (COMET, ClinicalTrials.gov identifier: NCT02926911) and RT technique (BONBIS, ClinicalTrials.gov identifier: NCT00907868; and Trans-Tasman Radiation Oncology Group [TROG] 07.01, ClinicalTrials.gov identifier: NCT00470236), will further refine the DCIS treatment paradigm.
In conclusion, although data continue to emerge regarding the management of DCIS, at this time RT following BCS remains the standard of care for most patients. RT has consistently been shown to decrease not only local recurrences but also invasive recurrences, which are associated with an increase in breast cancer mortality. Current tools, including prognostic scores and tumor genetics, have failed to identify a cohort for whom RT confers no benefit with respect to invasive recurrences. A diagnosis of DCIS warrants frank discussion between a physician and his or her patient, to enable shared decision making based on what absolute recurrence risk is deemed tolerable in light of patient preferences and comorbidities.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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