Is radiation indicated in patients with ductal carcinoma in situ and close or positive mastectomy margins?

Is radiation indicated in patients with ductal carcinoma in situ and close or positive mastectomy margins?

70% in patients with DCIS who met the criteria of E5194 (6.1% to 1.5% in the LIG cohort and 15.3% to 2% in the HG cohort). Additional follow-up is nec...

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70% in patients with DCIS who met the criteria of E5194 (6.1% to 1.5% in the LIG cohort and 15.3% to 2% in the HG cohort). Additional follow-up is necessary given that 70% of IBTRs occurred after 5 years. This article by Motwani and colleagues evaluating adjuvant whole breast irradiation (WBI) after breastconserving surgery (BCS) and the companion study published in the same issue of Cancer addressing the benefit of adjuvant accelerated partial breast irradiation (APBI) in patients with DCIS1 are quite thought provoking in the era of health care reform. Both studies were retrospective in nature. However, they both demonstrated a significant decrease in IBTR with the use of adjuvant RT, whether WBI or APBI, in well-selected patients with small lesions of DCIS who met the same selection criteria as the ECOG 5194 study where patients were treated with BCS without RT.2 It is obvious from all 3 studies that adjuvant RT is necessary for HG DCIS, as demonstrated by a recurrence rate of 15.3% at 5 years in the ECOG trial.2 However, the question still arises concerning the necessity of WBI or APBI after BCS for small, lowgrade DCIS lesions removed with generously clear margins. On the surface, although RT reduced the rate of local recurrence by more than 70%, the absolute recurrence rate without RT

Is radiation indicated in patients with ductal carcinoma in situ and close or positive mastectomy margins? Chan LW, Rabban J, Hwang ES, et al (Univ of California, San Francisco)

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in the ECOG trial was only 6.1% at 5 years. More concerning was the continued rise in the IBTR rate to 10.5% at 7 years.2 Therefore, a very thorough discussion with the patient is warranted about the role of adjuvant RT, using either WBI or APBI techniques, for LIG, mammographically detected, small DCIS lesions in terms of efficacy, toxicity, surveillance, and treatment in the setting of recurrence. Some patients would still elect for observation and would have a 90% chance of being recurrence free at 7 years. Others would choose to maximize their chances of not dealing with breast cancer for a second time. Since a survival advantage of adjuvant RT has not been demonstrated for DCIS,3-5 an individualized discussion of risks versus benefits of adjuvant RT is still required. E. S. Bloom, MD

References 1. Goyal S, Vicini F, Beitsch PD, et al. Ductal carcinoma in situ treated with breast-conserving surgery and accelerated partial breast irradiation: comparison of the Mammosite registry trial with intergroup study E5194. Cancer. 2011;117:1149-1155.

irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:5319-5324. 3. Bijker N, Meijnen P, Peterse JL, et al; EORTC Breast Cancer Cooperative Group, EORTC Radiotherapy Group. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853ea study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol. 2006;24: 3381-3387. 4. Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28:400-418. 5. Houghton J, George WD, Cuzick J, Duggan C, Fentiman IS, Spittle M; UK Coordinating Committee on Cancer Research, Ductal Carcinoma in situ Working Party, DCIS trialists in the UK, Australia, and New Zealand. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362:95-102.

2. Hughes LL, Wang M, Page DL, et al. Local excision alone without

Int J Radiat Oncol Biol Phys 80:25-30, 2011

Purpose.dResection margin status is one of the most significant factors for local recurrence in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery with or without radiation. However, its impact on

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chest wall recurrence in patients treated with mastectomy is unknown. The purpose of this study was to determine chest wall recurrence rates in women with DCIS and close (<5 mm) or positive mastectomy margins in order to evaluate the potential role of radiation therapy.

Methods and Materials.dBetween 1985 and 2005, 193 women underwent mastectomy for DCIS. Fifty-five patients had a close final margin, and 4 patients had a positive final margin. Axillary surgery was performed in 17 patients. Median follow-up was 8 years. Formal pathology review was conducted to measure and verify margin status. Nuclear grade, architectural pattern, and presence or absence of necrosis was recorded. Results.dMedian pathologic size of the DCIS in the mastectomy specimen was 4.5 cm. Twenty-two patients had DCIS of >5 cm or diffuse disease. Median width of the close final margin was 2 mm. Nineteen patients had margins of <1 mm. One of these 59 patients experienced a chest wall recurrence with regional adenopathy, followed by distant metastases 2 years following skin-sparing mastectomy. The DCIS was high-grade, 4 cm, with a 5-mm deep margin. A second patient developed an invasive cancer in the chest wall 20 years after her mastectomy for DCIS. This cancer was considered a new primary site arising in residual breast tissue. Conclusions.dThe risk of chest wall recurrence in this series of patients is 1.7% for all patients and 3.3% for high-grade DCIS. One out of 20 (5%) patients undergoing skin sparing or total skin-sparing mastectomy experienced a chest wall recurrence. This risk of a chest wall recurrence appears sufficiently low not to warrant a recommendation for postmastectomy radiation therapy for patients with margins of <5 mm. There were too few patients with positive margins to draw any firm conclusions. The benefit of radiation for patients with DCIS who undergo a mastectomy with close/positive margins remains unclear. Given the small numbers of patients in this clinical situation, no prospective data exist, and the pub-

lished literature suggests that only a tiny fraction of these patients (<3%) will develop a local recurrence after mastectomy. The current study by Chan and colleagues contributes to the scant literature on this topic by reporting the outcomes of a large cohort of patients with DCIS treated with mastectomy alone (without radiation). They reported low recurrence rates concordant with several other smaller series: of the 193 cases of mastectomy for DCIS, 59 had close/positive (#5 mm) margins; 30 had high-grade disease, and after a median follow-up of 8 years, only 1 patient (1.7%) experienced a chest wall recurrence. Among those patients with high-grade disease, 3.3% experienced a chest wall recurrence. Given the low risk of recurrence, these authors concluded that radiotherapy is not warranted after mastectomy for pure DCIS. Another major contribution to the literature for this clinical scenario is a study by Rashtian and colleagues.1 Of their 574 patients with DCIS treated with mastectomy, 31 had close/positive margins (defined as #2 mm), and at a median follow-up of 61 months, 5/31 (16%) patients developed a local recurrence compared with the 1/49 (2%) patients with margins between 2.1 and 10.0 mm. Among patients with margins less than or equal to 2 mm, the absolute risk of recurrence was higher in patients with high-grade disease and comedonecrosis who were 60 years of age or younger. The authors of this study concluded that patients with DCIS and these unfavorable features may benefit from the addition of radiotherapy to their treatment regimen. So how do we make use of these conflicting data in the clinical setting? Given the paucity of published literature on this topic, it is difficult to make strong recommendations to a patient in this clinical situation, but it may be reasonable to say that a small risk of an invasive relapse after mastectomy for

DCIS does exist, and this risk appears to be reduced with radiation, which may (or may not) justify its use. It is significant that all of the chest wall recurrences in the Rashtian and colleagues study were invasive and that half of these patients developed distant metastases. Notably, the 1 chest wall recurrence in the Chan and colleagues study was also an invasive recurrence with nodal involvement; furthermore, 1 additional patient developed an invasive chest wall recurrence (albeit after 20 years) that the authors categorized as a “new primary” given the duration of time since surgery. Further supporting this line of thought are other, smaller case series of patients who received postmastectomy radiation for DCIS with close/positive margins. These studies suggest that with the addition of radiation, the recurrence risk approaches 0%.2,3 While the role of postmastectomy radiation for DCIS with close/positive margins remains controversial, a discussion regarding the pros and cons of adjuvant treatment should ultimately occur. When weighing the risks of an invasive chest wall recurrence with the adverse effects of chest wall irradiation for a given patient, the use of postmastectomy radiation may (or may not) be warranted, depending on the individual’s clinical scenario. O. Offor, MD M. S. Moran, MD

References 1. Rashtian A, Iganej S, Amy Liu IL, Natarajan S. Close or positive margins after mastectomy for DCIS: pattern of relapse and potential indications for radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72: 1016-1020. 2. Eulau SM, Beatty JD. The role of adjuvant radiotherapy after

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mastectomy in ductal carcinoma in situ, breast. Int J Radiat Oncol Biol Phys. 2007;69:S228.

3. Metz JM, Schultz DJ, Fox K, Glick J, Solin LJ. Long-term outcome after postmastectomy radiation therapy for

breast cancer patients at high risk for local-regional recurrence. Cancer J Sci Am. 1999;5:77-83.

SURGICAL TREATMENT Phase III randomized equivalence trial of early breast cancer treatments with or without axillary clearance in post-menopausal patients results after 5 years of follow-up Avril A, On behalf of the AXIL95 Group (Institut Bergonié, Bordeaux Cedex, France; et al) Eur J Surg Oncol 37:563-570, 2011

Background.dAxillary lymph node clearance (ALNC) improves locoregional control and provides prognostic information for early breast cancer treatment, but effects on survival are controversial. This multicentre, randomized pragmatic equivalence trial compares outcomes for post-menopausal early invasive breast cancer patients after locoregional treatment with ALNC and adjuvant therapies to outcomes after locoregional treatment without ALNC and adjuvant therapies. Methods.dFrom 1995e2005, women aged $50 years with early breast cancer (tumor #10 mm) and clinicallynegative axillary nodes were randomized to receive treatment with ALNC (Ax) or without (no-Ax). Adjuvant therapies were prescribed according to hormonal receptor status and individual histological results. The primary endpoint was overall survival (OS); secondary endpoints were event-free survival (EFS) and functional outcomes.

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The trial was terminated due to lack of equivalence and low accrual after first interim analyses. Trial registration NCT00210236. Results.dOf 625 patients, 297 noAx and 310 Ax patients were maintained for final per-protocol analyses. OS and EFS at five years were not equivalent (Ax vs. no-Ax: 98% vs. 94% and 96% vs. 90% respectively). Recurrence was higher for no-Ax, particularly in the first five years after surgery. Axillary nodes were positive for 14% Ax patients but only 2% noAx patients experienced axillary node recurrence. Functional impairments were greater after ALNC. Conclusion.dOur results fail to demonstrate equivalence of outcomes when ALNC is omitted from postmenopausal early breast cancer patient treatment. However the low locoregional recurrence rates warrant further examination over a longer duration, in particular to consider whether these would impact on survival. Before the introduction of sentinel lymph node biopsy (SLNB) into standard breast cancer treatment, several studies were initiated with the aim of identifying a subgroup of clinically node-negative breast cancer patients with favorable primary tumor characteristics for whom axillary lymph node dissection (ALND) might be safely omitted.1-3 Most of these studies involved smaller tumors (T1a,

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T1b, or T1c) in older women, with the expectation of minimal impact on locoregional disease and OS. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial underpinned the belief that ALND conferred no significant survival advantage in the absence of overt or progressive axillary disease. Nonetheless, this seminal trial was confounded by salvage mastectomy and had a power of only 70% and 40% to detect survival differences of 7% and 5%, respectively.4 Metaanalyses can partially overcome the problems of small patient populations and underpowering, but they cannot readily distinguish between the effects of removing nodal tissue per se and the influence of adjuvant treatments (radiotherapy and systemic therapies) on clinical outcomes. A large metaanalysis of 6 trials involving 3000 patients claimed a survival benefit of 5.4% with ALND,5 whereas another meta-analysis drew the opposite conclusion.6 Even though a clear survival advantage had not been demonstrated for ALND, it remained the standard treatment until the advent of SLNB. Omission of ALND was highly selective and based on clinician discretion; it was an attempt to reduce potential upper-limb morbidity when there were few perceived benefits of ALND in terms of survival, regional control, and choice of adjuvant therapy.