Radiation Oncology/Breast/DCIS

Ductal Carcinoma in Situ

Clinical Presentation

 * Ductal carcinoma in situ - by default not metastatic; up to 5% axillary LN+ probably due to undiagnosed invasive focus
 * Risk factors same as invasive BCA: FH, reproductive events, EtOH consumption

Imaging

 * Presenting abnormalities (Tabar, 1999):
 * microcalcifications 76%
 * asymmetric densities 10%
 * Size underestimated by 1-2cm compared to pathology

MRI
 * IRCIS Trial, France; 2019 (2010 - 2014) -- PMID 30811290 -- "Preoperative Breast Magnetic Resonance Imaging in Women With Local Ductal Carcinoma in Situ to Optimize Surgical Outcomes: Results From the Randomized Phase III Trial IRCIS." (Balleyguier C, J Clin Oncol. 2019 Apr 10;37(11):885-892. doi: 10.1200/JCO.18.00595. Epub 2019 Feb 27.)
 * Randomized. 360 patients, 10 hospitals. Biopsy-proven, microcalcifications or mass <30 mm. Arm 1) no MRI vs Arm 2) MRI
 * Outcome: Re-operation rate for close/positive margins MRI 20% vs control 27% (NS). Mastectomy rate 18% vs 17% (NS).
 * Conclusion: No sufficient surgical improvement to be clinically relevant

Pathology

 * 16-24 duct-lobular systems, culminating in collecting duct at the nipple; multiple lateral ductal anastomoses
 * Histologically very diverse, no easy way to grade, but typically 3 groups

Upstaging to Invasive Disease

 * Harvard; 2008 PMID 17891441 -- "Sentinel node biopsy is important in mastectomy for ductal carcinoma in situ." (Dominguez FJ, Ann Surg Oncol. 2008 Jan;15(1):268-73. Epub 2007 Sep 22.)
 * Retrospective. 179 patients, mastectomy with SLB for DCIS on initial biopsy.
 * Outcome: Size of DCIS were not recorded uniformly. Unsuspected invasive cancer in 11%; of these, 20% had SLN+. However, overall SLN+ in 11% (micromets 1%, ITCs 10%), suggesting 10% SLN+ (94% ITCs) in patients with DCIS only. Completion ALND in 3 patients, SLNB was the only positive node in all of them
 * Conclusion: 11% of DCIS patients had invasive disease; use of SLND allowed them to avoid axillary dissection

Natural history

 * Considered rare until 1980's, prior to advent of population-wide mammographic screening
 * Autopsy series show rates <1% - 13%
 * Cumulative lifetime risk: ~0.5%
 * Prevalence on screening mammograms: ~20%

Progression of DCIS into invasive cancer:
 * Cumulative progression rate after biopsy in 7 studies: 36%. Most occur within 10 years, but some >15 years
 * Development of invasive CA (10-year rates): after BCS only ~15%, after BCS+RT ~8%
 * Nurses' Health Study, 2005 - PMID 15770688 &mdash; "Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses' Health Study." Collins LC et al. Cancer. 2005 May 1;103(9):1778-84.
 * 13 pts with DCIS later identified in breast biopsy originally thought benign. 6 pts developed invasive cancer (OR 13.5) and 10 pts developed either an invasive or in-situ lesion (OR was 20.1).

Mastectomy

 * Locoregional failure rate 4% or less, cancer specific mortality <4%
 * No randomized study comparing mastectomy with BCT

Surgical Margin

 * MDACC; 2013 (1996-2009) PMID 23975313 -- "Incidence and consequence of close margins in patients with ductal carcinoma-in situ treated with mastectomy: is further therapy warranted?" (Fitzsullivan E, Ann Surg Oncol. 2013 Dec;20(13):4103-12.)
 * Retrospective. 810 pts.
 * 94 pts with close margins (<3 mm), including 5 with positive margins, 54 with margins <= 1 mm, and 35 with margins > 1 mm.
 * 10-year LRR rate: 5.0% for margin <= 1mm, 3.6% for >1 and <3 mm, and 0.7% for >= 3 mm (SS).
 * Conclusion: "Close margins occur in a minority of patients undergoing mastectomy for DCIS and is the only independent risk factor for LRR. As the LRR rate in patients with close margins is low and less than the rate of contralateral breast cancer, PMRT is not warranted except for patients with multiple close/positive margins that cannot be surgically excised."


 * Harvard; 2012 (1998-2005) PMID 22975615 -- "Impact of Margin Status on Local Recurrence After Mastectomy for Ductal Carcinoma In Situ." (Childs SK, Int J Radiat Oncol Biol Phys. 2012 Sep 10.)
 * Retrospective. 142 pts underwent mastectomy without RT for pure DCIS (without microinvasion).
 * positive margin: 21 (15%). close margin (<= 2 mm): 23 (16%). Deep margin (close 14, positive 6). Superficial margin (close 13, positive 19).
 * Median f/u 7.6 yr.
 * Chest wall recurrence 2/142 (1.4%) -- 1/21 (4.8%) for positive margins, 1/23 (4.3%) for close margins, 0/98 for negative margins.
 * Conclusion: "Mastectomy for pure DCIS resulted in a low rate of local or distant recurrences. Even with positive or close mastectomy margins, the rates of chest wall recurrences were so low that PMRT is likely not warranted."


 * UC San Francisco; 2010 (1985-2005) PMID 20646871 -- "Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins?" (Chan LW, Int J Radiat Oncol Biol Phys. 2010 Jun 18. [Epub ahead of print])
 * Retrospective. 193 patients underwent mastectomy. DCIS median size 4.5 cm. Surgical margin: 55 close SM, 4 SM+. Median F/U 8 years
 * Outcome: Chest wall recurrence 1/59 close/positive SM (patient had 4 cm, G3 DCIS, SM 5 mm, skin-sparing mastectomy).
 * Conclusion: Risk of chest wall recurrence low for patients with margin <5 mm; not enough cases with positive margin


 * Southern California Permanente; 2008 (1994-2002) PMID 18954711 -- "Close or positive margins after mastectomy for DCIS: pattern of relapse and potential indications for radiotherapy." (Rashtian A, Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1016-20.)
 * Retrospective. 80 patients, DCIS treated with mastectomy without RT, with margins <10 mm. SM &le;2 in 39%, SM 2.1-10 61%. Median F/U 5 years
 * Outcome: Local recurrence 7%; if SM &le; 2 mm 16% vs SM >2 mm 2% (SS). Of the 6 patients with LR, 5 had G3 DCIS and/or comedonecrosis. All were <60 years
 * Conclusion: Greater than expected local recurrence in patients with <2 mm margin, particularly if they have high grade disease or comedonecrosis


 * Swedish Cancer Institute, Seattle; 2007 (1990-2006) ASTRO Abstract -- "The Role of Adjuvant Radiotherapy After Mastectomy in Ductal Carcinoma In Situ, Breast" (Eulau SM, Abstract 2043, 2007)
 * Retrospective. 16 patients, mastectomy for DCIS, adjuvant RT. Average DCIS size 6.8 cm, positive or &le; 1mm SM 7 patients, 1 mm SM 7 patients, &ge; 2 mm 2 patients (lesion size 10 and 15 cm). RT dose average 55.8 Gy (45 - 66.4). Median F/U 4.7 years
 * Outcome: LC 100%, DFS 100%, OS 100%
 * Toxicity: No lymphedema, decreased shoulder ROM 12%, chronic mild pain 12%. In 2 immediate reconstructions, both failed. In 2 delayed reconstruction, neither failed.
 * Conclusion: Excellent local control with RT despite close/positive margins and large lesions


 * Emory; 2007 PMID 17481544 -- "Local recurrence of ductal carcinoma in situ after skin-sparing mastectomy." (Carlson GW, J Am Coll Surg. 2007 May;204(5):1074-8; discussion 1078-80.)
 * Retrospective. 223 patients, DCIS treated with skin-sparing mastectomy and immediate reconstruction. No adjuvant RT. Mean F/U 6.9 years
 * Outcome: local recurrence 3.3%, regional recurrence 0.9%, distant recurrence 0.9%. If SM <1mm, local recurrence 10%. High grade also influenced LR
 * Conclusion: LR after skin-sparing mastectomy similar to total mastectomy. Re-excision of close SM should be performed and adjuvant RT should be considered

Wide excision alone

 * ECOG E-5194, 2009 (1997-2002)
 * 2009 PMID 19826126 "Local Excision Alone Without Irradiation for Ductal Carcinoma In Situ of the Breast: A Trial of the Eastern Cooperative Oncology Group." (Hughes LL, J Clin Oncol. published online ahead of print Oct 13 2009.)
 * Prospective, non-randomized. 670 pts. Low or intermediate grade DCIS 2.5 cm or less, or high grade DCIS 1 cm or less; surgical margins 3 mm or greater; no residual calcifications on postoperative mammography. Presence of comedo necrosis was categorized in the high grade group. Tamoxifen was allowed in those pts enrolled after 2000 (about 30% of pts received tamoxifen). Pathologic assessment was rigorous (sequential sectioning and complete embedding).
 * Median f/u 6.2 yrs(low-int;n=565) and 6.7 yrs(high grade;n=105). Median age 60; median tumor sizes 6mm (low/int grade) and 5mm (high grade). 5-yr ipsilateral breast events 6.1% (low/int) and 15.3% (high); 7-yr rate 10.5% (low/int) and 18.0% (high).
 * Conclusion: "Rigorously evaluated and selected patients with low- to intermediate-grade DCIS with margins 3 mm or wider had an acceptably low rate of ipsilateral breast events at 5 years after excision without irradiation. Patients with high-grade lesions had a much higher rate, suggesting that excision alone is inadequate treatment."
 * Comment: pathologic assessment included "complete sequential tissue processing". Their results may not be extrapolated to other centers using less rigorous pathologic assessment.
 * 10 year update ECOG 5194 (Solin SABCS 2012): 10 yr IBTR is is ~ 15% in both groups. http://cancerres.aacrjournals.org/content/71/24_Supplement/S4-6.short -- Median f/u 8.8 yr
 * 2015: 12 year PMID 26371148 -- "Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study." (Solin LJ, J Clin Oncol. 2015 Nov 20;33(33):3938-44.) -- Median f/u 12.3 yr
 * 12 yr rate of ipsilateral breast event (IBE) 14.4% (Cohort 1) and 24.6% (Cohort 2). Rate of invasive cancer: 7.5% and 13.4%.
 * Conclusion: "For patients with DCIS selected for favorable clinical and pathologic characteristics and treated with excision without radiation, the risks of developing an IBE and an invasive IBE increased through 12 years of follow-up, without plateau."

--8yr update LR 15.6%
 * Harvard, 2006 (1995-2002) - PMID 16461781 "Prospective study of wide excision alone for ductal carcinoma in situ of the breast." Wong JS et al. J Clin Oncol. 2006 Mar 1;24(7):1031-6.
 * Prospective, non-randomized. 158 pts. Pts with DCIS size <= 2.5 cm, grade 1-2. Necrosis allowed. Required wide excision with margins >= 1 cm. Tamoxifen not allowed.
 * Median f/u 40 mos. LR was 2.4%/yr, 5-yr rate of 12%. 69% of recurrences were DCIS and 31% were invasive cancer.
 * Conclusion: substantial risk of LRR with WLE without RT.

Surgical Margin

 * EBCTCG; 2010 (PMID 20956824)
 * 10-year IBTR (lumpectomy + RT): SM- 12% vs SM+ 24%
 * 10-year IBTR (lumpectomy alone): SM- 26% vs SM+ 44%
 * NSABP: 14 year IBTR (lumpectomy + RT): SM- 13% vs. SM+ 23%
 * MSKCC: 10 year IBTR (lumpectomy +/- RT): SM close 28% vs SM medium 21% vs SM wide 19%

Meta-Analysis
 * Dublin; 2009 PMID 19255332 -- "Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ." (Dunne C, J Clin Oncol. 2009 Apr 1;27(10):1615-20. Epub 2009 Mar 2.)
 * Meta-analysis. 4,660 patients, 22 trials evaluating BCS and RT.
 * Outcome: median time to IBTR 5 years. Recurrence 64% less if negative SM vs positive SM (OR 0.4, SS, using trial definition of negative margin, which ranged from no cells at ink to 10 mm). Margin thresholds for recurrence, &ge; 5-mm OR 1.0 vs 2-mm OR 1.5 (NS) vs 1-mm OR 2.9 (SS) vs no cells on ink OR 2.6 (SS).
 * Conclusion: Negative surgical margins should be obtained; 2mm margin a good cut-off

Studies
 * RAND Corporation; 2011 (1985-2000) PMID 21200025 -- "Comparative effectiveness of ductal carcinoma in situ management and the roles of margins and surgeons." (Dick AW, J Natl Cancer Inst. 2011 Jan 19;103(2):92-104. Epub 2011 Jan 3.)
 * Retrospective. 2 health systems: Monroe County, New York and Henry Ford Health System, Michigan. 994 women with DCIS, 50 treating surgeons. Evaluated surgical margin and treatments (BCS alone, BCS + RT, mastectomy), stratified by surgeon. Final SM positive 4.6%, close (&le; 2mm) 20.0%, negative 75.4%. Median F/U 5 years
 * Outcome: 5-year IBTR all ~6%, SM+ ~19%, SM close ~9%, SM negative 4% (SS). Surgeon performance accounted for 15-35% of 5-year IBTR and 13-30% of 10-year IBTR. 5-year DFS after mastectomy (99.3%), lumpectomy + RT (94.5%), and lumpectomy without RT (82.4%) significantly different by surgeon. IBTR risk: BCS no RT SM- 1.0; RT 0.25, BCS SM+ 3.4, SM close 1.4, mastectomy SM- 0.03, mastectomy SM close 0.4, mastectomy SM+ 2.0
 * Surgeon impact: If surgeon effect were improved to mean, IBTR reduction by 15%; if median, IBTR reduction by 22%, and if at 75th percentile, IBTR reduction by 31%
 * Conclusion: Positive SM large impact on IBTR, even for mastectomy and BCS with RT. Extent of surgeon variation and its contribution to long-term outcomes are troubling


 * Memorial Sloan Kettering; 2010 (1991-1995) PMID 20224381 -- "The influence of margin width and volume of disease near margin on benefit of radiation therapy for women with DCIS treated with breast-conserving therapy." (Rudloff U, Ann Surg. 2010 Apr;251(4):583-91.)
 * Retrospective. 194 patients, DCIS, excision alone or excision + RT
 * Outcome: IBTR 10-year 22%, 15-years 29%. By SM, <1mm 28% vs 1-9 mm 21% vs &ge; 10 mm 19%. RT reduced IBTR by 62% (SS), if <1mm by 83% vs 1-9 mm by 70% vs &ge; 10mm by 24% (NS). High volume disease near margin (margin width, number of involved ducts at closest margin) associated with increased risk of IBTR in no RT group, and greater proportional benefit of RT in RT group
 * Conclusion: Effect of RT on IBTR influenced by disease volume near margin


 * Institut Curie; 2009 PMID 19386441 -- "Ductal carcinoma in situ of the breast with close or focally involved margins following breast-conserving surgery: treatment with reexcision or radiotherapy with increased dosage." (Monteau A, Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1021-8. Epub 2009 Apr 20.)
 * Retrospective. 208 women, DCIS, BCT with close (<2 mm) or involved margins. Re-excision 29% or RT + boost 71%. Median RT dose 67 Gy. Median F/U 7.4 years
 * Outcome: On re-excision, 56% residual DCIS and 6% residual IDC. 7-year LRF if re-excision 9.6% vs RT + boost 9.3% (NS)
 * Conclusion: In selected patients, re-excision may be avoided by increasing RT dose to tumor bed to at least 66 Gy


 * NSABP B-24 (Julian TB, ASCO Breast Cancer Symposium 2007) Abstract
 * Retrospective analysis. 1569/1799 patients analyzed, 692 (44%) received optional boost. Majority boost 10 Gy (1-20 Gy) after 50 Gy whole breast. Mean F/U 14 yrs
 * Outcome: IBTR SM- 13% vs. SM+ 23% (SS). By margin status, if SM- boost 13% vs no boost 13% (NS), if SM+ boost 21% vs. no boost 26% (NS). On multivariate analysis, boost not significant predictor for recurrence; while age, SM status, comedo necrosis were significant predictors
 * Conclusion: Surgical margin status significant predictor for recurrence

BCS +/- RT

 * 10-year local recurrence: 25-30% BCS alone vs. ~15% BCS + RT (~50% reduction)
 * Invasive recurrence: ~16% vs. ~8% (~50% reduction)
 * Non-invasive ~15% vs. ~8% (40-50% reduction)
 * Based on NSABP B-17 data, annual IBTR recurrence rate is ~4% per year with surgery alone (2% invasive and 2% noninvasive); adjuvant RT decreases it to ~2% per year
 * Based on 3 randomized trials (NSABP B-17, EORTC 10853, and UKCCCR), all subgroups (as analyzed by multivariate analysis looking at individual variables) benefit from RT. These data have not been analyzed for subgroups defined by several variables (such as <40 and intermediate grade and large size).
 * Some retrospectively-defined prognostic groups (such as Van Nuys, see Prognosis section below) suggest there are discrete patient groups that may have different outcomes, and may benefit from different treatments:
 * "Low risk" patients - RT does not offer much if any additional benefit over BCS alone. These patients could potentially be treated with BCS alone
 * "High risk" patients - while RT does offer significant benefit, the rate of recurrence is still unacceptably high. These patients should probably be treated with mastectomy
 * In clinical practice in US, ~30% DCIS patients are treated with BCS alone, ~40% are treated with BCS+RT, and ~30% are treated with mastectomy. These rates vary widely with geography
 * Unfortunately, there are no commonly accepted guidelines to help stratify patients


 * NSABP B-17 & B-24, Long Term; 2011 (1985-1994) PMID 21398619 -- "Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS." (Wapnir IL, J Natl Cancer Inst. 2011 Mar 16;103(6):478-88. Epub 2011 Mar 11.)
 * Joint analysis of 2 trials. Median F/U B17 17.2 years and B-24 13.6 years
 * Outcome: Invasive breast ca 54% of recurrences. 15-year incidence of invasive IBTR for lumpectomy 19%, lumpectomy + RT (B-17) 8.9%, lumpectomy + RT (B-24) 10%, lumpectomy + RT + TAM (B-24) 8.5%. 15-year contralateral breast CA no TAM ~10% vs with TAM 7.3%. Invasive IBTR associated with 1.7x risk of death (SS), DCIS IBTR no difference in mortality risk. Incidence of breast CA death ~3% overall (lumpectomy only (B-17) 3.1%, lumpectomy + RT 4.7% (B-17), lumpectomy + RT 2.7% (B-24), lumpectomy + RT + TAM (B-24) 2.3%
 * Conclusion: Long-term prognosis remains excellent, invasive IBTR increases risk for BCA-related death


 * EBCTCG DCIS; 2010 PMID 20956824 -- "Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast." (Correa C, J Natl Cancer Inst Monogr. 2010;2010(41):162-77.)
 * Meta-analysis. Individual patient data for 4 randomized trials. 3729 women. 10-year data
 * Outcome: 10-year IBTR no RT 28% vs RT 13% (SS), benefit greater in women >50 (28% vs 11%) compared with women <50 (29% vs 18%), no difference based on any other factor. Women with small, low-grade tumors and negative SM still benefited (30% vs 12%, SS)
 * Outcome: No effect on BCA mortality (~4%), other-cause mortality (~5%), and all-cause mortality (~8%)


 * RTOG 98-04 -- RT vs. No RT
 * Randomized. Closed due to poor accrual.. "Good risk" DCIS, < 2.5 cm, margins > 3mm, grade I-II / III, necrosis in < 1/3 of the ducts. Arm 1) RT vs. Arm 2) no RT. Radiotherapy to the whole breast consists of a choice of 50.4 Gy in 1.8 Gy fractions, 50 Gy in 2 Gy, or 42.5 Gy in 16 fx. Tamoxifen at 20 mg qd x 5 yrs (choice of physician).
 * "J Clin Oncol 30, 2012 (suppl; abstr 1004)' -- RT vs. No RT" 98-04.  636 randomized. 1790 planned accrual.  2 LF in the RT arm vs. 15 in the OBS arm: at 5 years 0.4% RT vs. 3.2% OBS. TAM was used in 62% of women.  In this “good risk” subset of DCIS, the LF rate was decreased significantly with the addition of RT.
 * 7-years; 2015 PMID 25605856 -- "RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation." (McCormick B, J Clin Oncol. 2015 Mar 1;33(7):709-15). " LF rate was 0.9% (95% CI, 0.0% to 2.2%) in the RT arm versus 6.7% (95% CI, 3.2% to 9.6%) in the observation arm (hazard ratio, 0.11; 95% CI, 0.03 to 0.47; P < .001).


 * NSABP B-17
 * Randomized. 818 women with DCIS, SM-. Treated with lumpectomy or lumpectomy + RT 50Gy (no boost)
 * 5-years; 1993 PMID 8292119 -- "Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer." (Fisher B, N Engl J Med. 1993 Jun 3;328(22):1581-6.). Mean f/u 3.6 years
 * 5-year EFS: 74% vs. 84% (SS). Benefit due to reduction in 2nd ipsilateral BCA
 * 5-year IBTR: invasive 10.5% vs. 2.9%, noninvasive 10.4% to 7.5%
 * 8-years; 1998 PMID 9469327 -- "Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. (Fisher B, J Clin Oncol. 1998 Feb;16(2):441-52.) F/U 7.5 years
 * 8-year IBTR: invasive 13.4% vs. 3.9% (SS), noninvasive 13.4% vs. 8.2% (SS). All cohorts benefited.
 * 10-years; 2001 PMID 11498833 -- "Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience." (Fisher B, Semin Oncol. 2001 Aug;28(4):400-18.) Update on B-17 and B-24. F/U 12 years
 * 10-year IBTR: 30.8% vs. 14.9% (57% reduction); Invasive 16.4% to 7.1% (62% reduction)
 * No difference in distant recurrence or contralateral breast cancers.
 * MVA: Moderate/marked comedo necrosis and uncertain/positive margins predictive of IBT recurrence.
 * 12-years; 2005 PMID 15752884 -- "Cost-effectiveness of radiation therapy following conservative surgery for ductal carcinoma in situ of the breast." (Suh WW, Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1054-61.)
 * 12-year rates: invasive 18% vs. 8%, noninvasive 16% vs. 9%
 * RT incemental cost: overall $3300 (2002 Medicare schedule), initial $8700, due to higher LR salvage costs.
 * Incremental cost-effectiveness rate (ICER): $36,700 per QALY
 * Conclusion: should not withold RT because of cost-effectiveness
 * 15 years - see "NSABP B-17 & B-24, Long Term; 2011"
 * Criticisms: margins status criteria, no radiographic eval postop(silverstein)
 * Criticism by Fisher of VNPI: Has not been validated, can not be applied to B-17 because patients have tumors >=4.1cm. "The likelihood of identifying a single biological marker or combination of markers that can identify with precision the 13% of women with focal, mammographically detected DCIS who will develop an invasive breast cancer after lumectomy, let alone the small number (4%) [that will not], seems remote."


 * EORTC 10853 (1986-1996) -- RT vs. No RT
 * Randomized. 1010 women with DCIS. Size <=5cm. SM- (intraop evaluation of margins, re-excision if needed). Lumpectomy alone to lumpectomy + RT 50 Gy
 * 10-years; 2006 PMID 16801628 &mdash; "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 10853--A Study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group." (Bijker N, J Clin Oncol. 2006 Jul 20;24(21):3381-7.). Median F/U 10.5 yrs.
 * 10-year LR: 26% BCS alone vs 15% BCS+RT (SS), 47% reduction. All subgroups benefited.
 * 10-year LR: invasive 13% vs. 8% (SS), 42% reduction; DCIS 14% vs. 7% (SS), 48% reduction
 * Increased risk for LR: age <40, grade 2 or 3, cribiform or solid growth pattern, doubtful margin, and LE alone. Size not a prognostic factor
 * No difference in OS or distant mets
 * 2000 PMID 10683002 &mdash; "Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group." Julien JP et al. Lancet. 2000 Feb 12;355(9203):528-33. Median follow-up 4.25 years
 * 4 year LR-free rate: 84% BCS vs. 91% BCS + RT (SS). Invasive cancer reduced 8% to 4%, DCIS reduced 8% to 5% with RT
 * 4 year mets-free rate: 98% vs. 99%
 * Contralateral breast cancer 99% lumpectomy alone and 97% with RT (SS). * they did not elaborate on the use of their wedges but 4.5 years is too early to see RT induced breast cancer*


 * UKCCCR (1990-1998) -- Observation vs RT vs TAM vs RT + TAM
 * Randomized. 1701 women with DCIS. 2x2 factorial (921 randomized to fully 2x2, the remainder one way randomization to +/- RT or +/- TAM): BCS followed by 1) observation, 2) RT alone, 3) tamoxifen alone, or 4) RT + Tamoxifen. RT to 50 Gy, TAM 20mg qd x5 years
 * 5-years; 2003 PMID 12867108 -- "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." (Houghton J, Lancet. 2003 Jul 12;362(9378):95-102.). Mean F/U 4.4 years
 * Outcome: Breast events: OBS 22% vs. TAM alone 18% vs. RT alone 8% vs. TAM+RT 6%. Too few deaths for meaningful analysis.
 * RT: benefit for invasive IBTR (3% vs. 6%, HR 0.45), and benefit for ipsilateral DCIS (3% vs. 7%, HR 0.36), no impact on contralateral events. New breast events reduced 16% to 7% (SS)
 * Tamoxifen randomization: no impact on invasive IBTR (7% vs. 7%), no impact on ipsilateral DCIS (7% vs. 10%), benefit for bilateral DCIS (7% vs 11%, HR 0.68)
 * Subgoup analysis: No synergy between tamoxifen and RT. No benefit of tamoxifen differs from B-24 trial: authors suggest it may be due to differences in the patient population. In B-24 33.5% of patients were under 50 compared to only 9.5% in the UK/ANZ trial
 * Conclusion: RT can be recommended for DCIS, there is little evidence to recommend tamoxifen


 * Swedish DCIS Trial (1987-1999) -- RT vs No RT
 * Randomized. 1046 women, DCIS on sector resection, target clinical surgical margin 1 cm but microscopically negative SM not required; clinically N0. Arm 1) RT 50/25 vs Arm 2) no RT
 * 2008 PMID 18250350 -- "Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast." (Holmberg L, J Clin Oncol. 2008 Mar 10;26(8):1247-52. Epub 2008 Feb 4.)
 * Outcome: IBTR RT+ 12.1% vs RT- 27.1% (RR 0.4, SS), invasive recurrence ~50%. No difference in DMFS. Age effect: women <50 RR 0.7, age >50 RR ~0.3. No group defined by stratification variables that had low risk without RT
 * Conclusion: RT decreases risk by ~50%, though younger women have low protective effect and older women benefit substantially

BCS+RT Long-term outcomes

 * Multi-institutional PMID 15674853 -- "Long-term outcome after breast-conservation treatment with radiation for mammographically detected ductal carcinoma in situ of the breast." (Solin LJ, Cancer. 2005 Mar 15;103(6):1137-46.)
 * Retrospective. 1003 women with mammo-detected DCIS, treated with BCS+RT in 10 institutions. Median F/U 8.5 years
 * 15-year: OS 89%, cause-specific 98%, freedom from distant mets 97%, freedom from LR 81%
 * Multivariate predictors: age >50, negative final margin for better outcome (LR <8% vs. 19% overall)

Boost

 * No randomized trials published, 2 trials ongoing (TROG 07.01 and French BONBIS trial)


 * Multi-institutional; 2017 (1980-2010) PMID 28358936 -- "Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy." (Moran MS, JAMA Oncol. 2017 Aug;3(8):1061-8)
 * Retrospective. 4131 pts. Pooled analysis from 10 institutions in USA,Canada,France. Minimum 5 yrs f/u.
 * Median f/u 9 yrs. Boost associated with lower IBTR (HR 0.73), improved IBTR-free survival 97.1% (boost) vs 96.3% (no boost) at 5 yrs, 94.1% vs 92.5% at 10 yrs, 91.6% vs 88.0% at 15 yrs.
 * Conclusion: RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer


 * Toronto; 2013 (1994-2003) PMID 23708085 -- "Impact of boost radiation in the treatment of ductal carcinoma in situ: a population-based analysis." (Rakovitch E, Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):491-7. doi: 10.1016/j.ijrobp.2013.02.031.)
 * Retrospective. Ontario registry. 1895 patients with DCIS, treated by BCS and RT. 70% treated with hypofractionated regimens (40-44 Gy in 16 fxs). 561 received boost.
 * Outcome: 10-year LR boost 13% vs no boost 12% (NS); 10-year invasive LR 6% vs 7% (NS); DCIS 5% vs 7% (NS). No benefit to boost on MVA (HR 0.8, NS). No benefit for patients <45 as per Rare Cancer Network study
 * Conclusion: Radiation boost not associated with lower risk of local or invasive recurrence


 * McGill; 2012 (2000-2006) PMID 21664063 -- "Ductal carcinoma in situ--the influence of the radiotherapy boost on local control." (Wong P, Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):e153-8.)
 * Retrospective. 220 pts, all treated with lumpectomy + RT. 36% received a boost.
 * Median f/u 46 mo. Pts in the boost group more frequently had positive margins or margins < 1 mm (48% vs 8%) and more frequently were in a higher risk Van Nuys Prognostic Index category.
 * Local recurrence: 0/79 (boost) vs 8/141 (no boost). The presence of necrosis significantly correlated with LR.
 * Conclusion: Our results suggest that the use of a radiotherapy boost improves local control in DCIS and may outweigh the poor prognostic effect of necrosis.


 * NSABP B-24 Abstract -- "Is boost therapy necessary in the treatment of DCIS" (Julian TB, ASCO Breast Cancer Symposium 2007, Abstract 146.)
 * Retrospective analysis. 1569/1799 patients analyzed, 692 (44%) received optional boost. Majority boost 10 Gy (1-20 Gy) after 50 Gy whole breast. Mean F/U 14 yrs
 * Subgroup characteristics: boost group more likely to have SM+ 46% vs. 37% (SS), or comedo necrosis 42% vs. 35% (SS)
 * Outcome: IBTR boost 14% vs. no boost 15% (NS). IBTR SM- 13% vs. SM+ 23% (SS). By margin status, if SM- boost 13% vs no boost 13% (NS), if SM+ boost 21% vs. no boost 26% (NS). On multivariate analysis, boost not significant predictor for recurrence; while age, SM status, comedo necrosis were significant predictors
 * Conclusion: Boost had no significant impact on recurrence


 * Rare Cancer Network (1978-2004) PMID 16887482 -- "Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network." (Omlin A, Lancet Oncol. 2006 Aug;7(8):652-6.)
 * Retrospective. 373 women age 45 or younger from 18 institutions. TisN0, <=45, BCS. 15% no RT, 45% RT 50 Gy, 40% RT 50 Gy + 10 Gy boost. Median F/U 6 years
 * LR rate: 15%, LR-free survival at 10 years: No RT 46% vs. 72% RT no boost vs. 86% RT boost (SS)
 * Predictors: age <40, margin, RT dose
 * Conclusion: consider boost in patients <=45 years
 * Comment: substantial proportion of patients unknown margin, grade, or size. 6 yr f/u but 10 yr results

Hypofractionation

 * University of Toronto; 2014 (1994-2003) PMID 25220719 -- "Long-term outcomes of hypofractionation versus conventional radiation therapy after breast-conserving surgery for ductal carcinoma in situ of the breast." (Lalani N, Int J Radiat Oncol Biol Phys. 2014 Dec 1;90(5):1017-24. doi: 10.1016/j.ijrobp.2014.07.026. Epub 2014 Sep 11.)
 * Retrospective. 1609 patients treated in Ontario. Conventional (50/25) in 60% vs hypofractionated (42.4/16) in 40%. Boost in 30% (15% of CF and 54% of HF). Median F/U 9.2 years
 * Outcome: 10-year LRFS CF 86% vs HF 89% (p=0.03), but not SS on multivariate analysis
 * Conclusion: Risk of local recurrence similar after hypofractionated or conventional radiation


 * Princess Margaret; 2010 (1999-2004) PMID 20400190 -- "Local control with conventional and hypofractionated adjuvant radiotherapy after breast-conserving surgery for ductal carcinoma in-situ." (Williamson D, Radiother Oncol. 2010 Jun;95(3):317-20. Epub 2010 Apr 17.)
 * Retrospective. 266 patients, conventional 50/25 (39%) or hypofractionated 42.4/16 or 40/16 + 12.5 Gy boost (61%) WBRT after BCS for DCIS. Median F/U 3.8 years
 * Outcome: 4-year recurrence conventional 6% vs hypo-fx 6.7% (NS). High grade increased risk of LR (11% for Gr3 vs 4% for Gr 1/2, SS)
 * Conclusion: Hypofractionated WBRT for DCIS has comparable local control, and should be considered in this patient group

APBI

 * Please also see the main Radiation Oncology/Breast/Partial breast irradiation page


 * American Society of Breast Surgeons; 2010 (2002-2004) PMID 20577822 -- "Update on DCIS Outcomes from the American Society of Breast Surgeons Accelerated Partial Breast Irradiation Registry Trial." (Jeruss JS, Ann Surg Oncol. 2010 Jun 25. [Epub ahead of print])
 * Registry trial. 194 patients, DCIS, MammoSite registry. Placement at lumpectomy 45%, post-lumpectomy 55%. SLN 26%. SM negative 88%, <2 mm 11%, positive 1%. Grade 3 37%. Median F/U 4.5 years
 * Outcome: IBTR 3.1%, breast/axilla recurrence 0.5%, 5-year local recurrence 3.4%
 * Toxicity: Seroma 24%, associated with lumpectomy placement. Favorable cosmesis 92% (minimum 5 year follow-up)
 * Conclusion: APBI via MammoSite well tolerated for patients with DCIS

BCS+RT +/- Tamoxifen

 * Benefit in B-24, no benefit in UKCCR until after long-term follow-up.


 * NSABP B-24
 * Randomized. 1804 women with DCIS ± LCIS (LCIS also present in ~5%), SM+ allowed (15%). Age <50 in 33%. Did not require tumors to be ER+. BCS + RT with or without tamoxifen. RT 50 Gy (no boost). TAM 20mg QD (noncompliance 31%).
 * 5-years; 1999 PMID 10376613 -- "Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial." (Fisher B, Lancet. 1999 Jun 12;353(9169):1993-2000.) Median F/U 6.2 years
 * 5-year BCA events: 13.4% vs tamoxifen 8.2% (SS), ipsilateral 9.5% vs. 6.0% (SS), contralateral 3.4% vs. 2.0% (SS)
 * 5-year invasive: 7.2% vs 4.1% (SS), ipsilateral 4.2% vs. 2.1% (SS), 2.3% vs. 1.8% (NS)
 * Younger patients (<50): IBTR placebo 16% vs. TAM 11%; older patients 6% vs. 5%
 * Conclude: Tamoxifen of benefit for further reduction of invasive breast cancer recurrences. There was no difference in regional or distant metastases.
 * Authors suggest that RT+tam concurrent is of benefit but a recent paper in JCO disputes this theory. (Ahn et al, JCO, 2005)
 * Use of ER; 2002 (No PMID) "Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP Protocol B-24." Allred DC et al. Breast Cancer Res Treat 2002;76(suppl):S36.
 * For findings, see commentaries at and.
 * Retrospective analysis. For DCIS with ER-, no benefit seen for tamoxifen.
 * 15 years - see "NSABP B-17 & B-24, Long Term; 2011"
 * Use of ER; 2012 No PMID yet Abstract -- "Adjuvant Tamoxifen Reduces Subsequent Breast Cancer in Women With Estrogen Receptor–Positive Ductal Carcinoma in Situ: A Study Based on NSABP Protocol B-24." (Allred DC, Online before print -- JCO March 5, 2012)
 * Retrospectively measured ER and PR in 732 pts (41%) at central lab and determined receptor status for an additional 283 pts (16%) at local institutions.
 * ER was + in 76% of pts. Pts with ER-positive DCIS treated with Tam showed significant decreases in subsequent breast cancer at 10 yrs (HR 0.49). Similar results were seen when ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately. No significant benefit seen for ER-negative DCIS.
 * Conclusion: Patients in NSABP B-24 with ER-positive DCIS receiving adjuvant tamoxifen after standard therapy showed significant reductions in subsequent breast cancer.


 * UKCCCR (1990-1998) -- Observation vs RT vs TAM vs RT + TAM
 * Randomized. 1701 women with DCIS. 2x2 factorial (921 randomized to fully 2x2, the remainder one way randomization to +/- RT or +/- TAM): BCS followed by 1) observation, 2) RT alone, 3) tamoxifen alone, or 4) RT + Tamoxifen. RT to 50 Gy, TAM 20mg qd x5 years
 * 5-years; 2003 PMID 12867108 -- "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." (Houghton J, Lancet. 2003 Jul 12;362(9378):95-102.). Mean F/U 4.4 years
 * Outcome: Breast events: OBS 22% vs. TAM alone 18% vs. RT alone 8% vs. TAM+RT 6%. Too few deaths for meaningful analysis.
 * RT: benefit for invasive IBTR (3% vs. 6%, HR 0.45), and benefit for ipsilateral DCIS (3% vs. 7%, HR 0.36), no impact on contralateral events. New breast events reduced 16% to 7% (SS)
 * Tamoxifen randomization: no impact on invasive IBTR (7% vs. 7%), no impact on ipsilateral DCIS (7% vs. 10%), benefit for bilateral DCIS (7% vs 11%, HR 0.68)
 * Subgoup analysis: No synergy between tamoxifen and RT. No benefit of tamoxifen differs from B-24 trial: authors suggest it may be due to differences in the patient population. In B-24 33.5% of patients were under 50 compared to only 9.5% in the UK/ANZ trial


 * 12.7 years; 2011 PMID 21145284 --"Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial." (Cuzick J, Lancet. 2011 Jan;12(1):21-9.). Mean F/U 12.7 years
 * Conclusion: RT can be recommended for DCIS, there is little evidence to recommend tamoxifen for prevention of ipsilateral invasive disease.

BCS+RT +/- Herceptin

 * NSABP B-43
 * Randomized, Phase III trial. 2,014 patients with DCIS, HER2+. Arm 1) BCS + RT vs Arm 2) BCS + RT + Trastuzumab
 * Initial results; 2021 PMID 33739848 -- "Comparison of Radiation With or Without Concurrent Trastuzumab for HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy: A Phase III Clinical Trial", Cobleigh M, J Clin Oncol 2021 Jul 20;39(21):2367-2374. Median F/U 6.6
 * Outcome: IBTR in RT 6% vs RT+H 5% (HR 0.8, p=NS). Invasive IBTR 2% vs 2% (NS).
 * Conculsion: Modest but not significant 19% reduction in IBTR with Herceptin

Multi-focal DCIS

 * Toronto; 2007 (1982-2000) PMID 17984188 -- "Significance of multifocality in ductal carcinoma in situ: outcomes of women treated with breast-conserving therapy." (Rakovitch E, J Clin Oncol. 2007 Dec 10;25(35):5591-6. Epub 2007 Nov 5.)
 * Retrospective. 615 cases of DCIS (multifocal n=260, unifocal n=314, unreported n=31), treated with BCS alone (50%) or BCS+RT (50%); most RT 50/25, some 40/16
 * Outcome: local recurrence BCS alone 21% (50% invasive) vs. BCS+RT 9% (24% invasive); 10-year LRFR BCS alone 72% vs. BCS+RT 82%. Median time-to-recurrence BCS alone 4.3 years vs. BCS+RT 3.0 years
 * Multifocality: 10-year LRFR multifocal 59% vs. unifocal 80% (SS); but if treated with BCS+RT, no difference (80% vs. 87%, NS)
 * Conclusion: Multifocality significant predictor of local recurrence if BCS only; no difference if adjuvant RT used

Prognosis
Oncotype DCIS
 * University of Toronto; 2019 PMID 30190195 -- "Including the Ductal Carcinoma-In-Situ (DCIS) Score in the Development of a Multivariable Prediction Model for Recurrence After Excision of DCIS." (Paszat L, Clin Breast Cancer. 2019 Feb;19(1):35-46. doi: 10.1016/j.clbc.2018.07.018. Epub 2018 Jul 29.)
 * Retrospective. 1102 patients from Ontario. Models for LR developed: 1) clinicopathologic (CPF), 2) clinicopathologic + ER + HER2 status (CPF+receptors), 3) clinicopathologic + DCIS score (CPF+DS).
 * Outcome: Strongest prediction model CPF+DS (0.70) vs CPF+receptors (0.69) vs CPF (0.68). Better at calibrating low (<10%) LR at 10 years
 * Conclusion: Individual prediction of LR more accurate for low risk women to omit RT when incorporating DCIS score

Van Nuys Prognostic Classification (VNPI)


 * 2010 Update (-2009) PMID 20956828 -- "Choosing treatment for patients with ductal carcinoma in situ: fine tuning the University of Southern California/Van Nuys Prognostic Index." (Silverstein MJ, J Natl Cancer Inst Monogr. 2010;2010(41):193-6.)
 * 949 pts with DCIS, 604 excision alone, 345 excision + RT. No hormonal therapy. Used the updated USC / Van Nuys scoring system (size, margin, DCIS classification, age) which gives scores 4-12. Goal is to update the treatment recommendations to achieve a LR risk of <20% at 12 yrs.
 * Outcomes: Median f/u 86 months (7.1 yrs). 165 local recurrences (103 - excision alone, 62 - RT).
 * 12-yr local recurrence: score 4-6, <= 6% (NS difference for RT vs no RT); score 10-12, >= 40% (for excision + RT);
 * Original treatment recommendations: excision alone for those who score 4-6; RT for those who score 7-9; mastectomy for those who score 10-12.
 * New treatment recommendations: to achieve a LR risk of <20% at 12 yrs.


 * 2003 Update PMID 14682107 -- "An argument against routine use of radiotherapy for ductal carcinoma in situ." (Silverstein MJ, Oncology (Williston Park). 2003 Nov;17(11):1511-33; discussion 1533-4, 1539, 1542 passim.)
 * 706 patients with DCIS, 426 excision alone, 280 excision + RT.

VNPI Treatment guidelines :
 * 4-6 points: BCS alone
 * 7-9 points: BCS + RT
 * 10-12 points: Mastectomy


 * 1999 Subsequent report on margins: PMID 10320383 Full text, 1999 (1979-1998) &mdash; "The influence of margin width on local control of ductal carcinoma in situ of the breast." Silverstein MJ et al. N Engl J Med. 1999 May 13;340(19):1455-61.
 * Retrospective. 469 pts. Pts treated until 1989 received post-op RT and those treated after 1989 did not. RT was 40-50 Gy to whole breast + 16-20 Gy boost. Tumors were assessed for histologic subtype, nuclear grade, comedonecrosis, maximal diameter, and margin width. Margins were classified as close or involved (<1 mm), intermediate (1 to <10 mm), or wide.
 * RT decreased the recurrence rate for close or involved margins; for intermediate or wide margins, was not statistically different.
 * Conclusion: RT is not necessary for margins > 10 mm.


 * 1996 First report PMID 8635094 &mdash; "A prognostic index for ductal carcinoma in situ of the breast." Silverstein MJ et al (and Lewinsky BS). Cancer. 1996 Jun 1;77(11):2267-74.
 * Came up with Van Nuys Prognostic Index (VNPI). Combines tumor size, margin width, histologic classification. Score 1-3 for each to arrive at a total score of 3-9.
 * Evaluated 333 pts treated with excision alone or excision + RT.
 * For pts with VNPI score of 3-4, excellent recurrence free survival (100% vs 97%) whether or not RT was used. For VNPI scores of 5-7, there was a 17% decrease (85% vs 68%) in RFS when RT was used. For score of 8-9, recurrence rate > 60% despite RT.
 * Conclusion: recommend excision alone for score of 3-4, excision + RT for score of 5-7, and mastectomy for 8-9.

For older VPNI versions, please see the DCIS Van Nuys section

Alternative
 * PMID 16750316 -- "Rationalization and regionalization of treatment for ductal carcinoma in situ of the breast." (Smith GL, Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1397-403.) Used classification below for cohort study:


 * Low risk: 0
 * Intermediate risk: 1-2
 * High risk: 3-6

Guidelines

 * NIH State-of-the-Science
 * 2009 Web Page Statement
 * 2009 PMID 19784089 -- "NIH state-of-the-science conference statement: diagnosis and management of ductal carcinoma in situ (DCIS)." (Allegra CJ, NIH Consens State Sci Statements. 2009 Sep 24;26(2):1-27.)