Radiation Oncology/Breast/DCIS
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Ductal Carcinoma in Situ
Contents |
[edit] 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
[edit] Mammography
- Presenting abnormalities (Tabar, 1999):
- microcalcifications 76%
- asymmetric densities 10%
- Size underestimated by 1-2cm compared to pathology
[edit] 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
[edit] 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:
- Cummulative 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 — "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).
[edit] Mastectomy
- Locoregional failure rate 4% or less, cancer specific mortality <4%
- No randomized study comparing mastectomy with BCT
[edit] Wide excision alone
- 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.
[edit] Surgical Margin
- 14 year IBTR (lumpectomy + RT): SM- 13% vs. SM+ 23%
- 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
[edit] 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
- 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).
- NSABP B-17 -- RT vs. No RT
- 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
- 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 — "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 — "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) -- RT vs. No RT
- Randomized. 1701 women with DCIS. 2x2 factorial: 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
- Tamoxifen: no impact on invasive IBTR, benefit for DCIS IBTR (HR 0.68)
- RT: benefit for invasive IBTR (HR 0.45), and benefit for DCIS IBTR (HR 0.36). New breast events reduced 16% to 7% (SS)
- No synergy between tamoxifen and RT
[edit] 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)
[edit] Boost
- No randomized trials
- 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
- 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
[edit] BCS+RT +/- Tamoxifen
- Benefit in B-24, no benefit in UKCCR. Perhaps due to somewhat different patient populations / age
- NSABP B-24
- Randomized. 1804 women with DCIS or LCIS, SM+ allowed (15%). Age <50 in 33%. 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.
- UKCCCR (1990-1998)
- Randomized. 1701 women with DCIS. 2x2 factorial: BCS followed by 1) observation, 2) RT alone, 3) tamoxifen alone, or 4) RT + Tamoxifen. RT to 50 Gy, TAM 20mg qd x5 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
- Tamoxifen: no impact on invasive IBTR, benefit for DCIS IBTR (HR 0.68)
- RT: benefit for invasive IBTR (HR 0.45), and benefit for DCIS IBTR (HR 0.36). New breast events reduced 16% to 7% (SS)
- No synergy between tamoxifen and RT
- Note: 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.
[edit] 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
[edit] Prognosis
NCCN Guidelines
- RT for all patients after BCS, unless DCIS diameter is <0.5 cm
- Boost recommended for everyone getting RT
Van Nuys Prognostic Classification (VNPI)
- 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.
| Parameter | 1 Point | 2 Points | 3 Points |
|---|---|---|---|
| Size | <=15 mm | 16-40 mm | >40 mm |
| Grade | Grade I-II | Grade I-II + necrosis | Grade III |
| Margin | >= 10 mm | 1-9 mm | <1 mm |
| Age | >60 | 40-60 | <40 |
| Points | Overall LR | BCS Alone LR | BCS+RT LR | p-value |
|---|---|---|---|---|
| 4-6 | 3% | 3% | 3% | NS |
| 7-9 | 27% | 36% | 21% | SS |
| 10-12 | 66% | 88% | 41% | SS |
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) — "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 — "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:
| Parameter | Age | Size | Histology |
|---|---|---|---|
| 0 Points | 61+ | <=15 mm | Grade I-II |
| 1 Points | 40-60 | 16-40 mm | Grade I-II + Necrosis |
| 2 Points | <40 | >40 mm | Grade III |
- Low risk: 0
- Intermediate risk: 1-2
- High risk: 3-6
