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The Impact of Surgery, Radiation, and Systemic Treatment on Outcomes in Patients With Ductal Carcinoma In Situ

The Impact of Surgery, Radiation, and Systemic Treatment on Outcomes in Patients With Ductal... Abstract Background Ductal carcinoma in situ (DCIS) is associated with low rates of mortality. Outcomes are generally assessed in terms of recurrence. Methods Published studies were abstracted from MEDLINE and other sources. We include articles published through January 31, 2009; 10 publications of five randomized controlled trials and 133 publications of 64 observational studies were reviewed. Results Whole-breast radiation therapy following breast-conserving surgery (BCS) was consistently associated with a reduced incidence of local DCIS recurrence and local invasive carcinoma. Women undergoing mastectomy were less likely than women undergoing lumpectomy with or without radiation to experience local DCIS or invasive recurrence. Tamoxifen use reduced risk of recurrent DCIS or invasive carcinoma. Conclusions BCS plus radiation and mastectomy appear to yield equivalent outcomes, whereas BCS alone tends to be inferior to mastectomy. Tamoxifen seems helpful in treating DCIS. Background Because ductal carcinoma in situ (DCIS) is associated with low rates of mortality, analyses of the success of treatment must focus on recurrence. The basic treatment decisions reflect those for invasive breast cancer: mastectomy and breast-conserving surgery (BCS) with or without radiation. Chemotherapy is not in the repertoire. However, adjuvant therapy with tamoxifen is. Methods We used the methods described in detail by Virnig (1). We identified 10 publications from five randomized controlled trials and 133 reports from observational studies that were published from 1965 through January 31, 2009. This article includes a highly abbreviated reference list. Results The most consistently measured outcomes were ipsilateral DCIS, ipsilateral invasive cancer, combined ipsilateral DCIS and invasive cancer, contralateral DCIS, contralateral invasive cancer, combined contralateral DCIS and invasive cancer, breast cancer mortality, all-cause mortality, chemotherapy use, local recurrence, regional recurrence, distant recurrence, and other outcomes. For the purposes of this report, we consider BCS, lumpectomy, and wide local excision to be analogous terms. BCS With Radiation In several randomized trials, whole-breast radiation therapy (RT) following BCS was consistently associated with a reduced incidence of local DCIS recurrence and local invasive carcinoma but with no impact on breast cancer mortality or total mortality (2–4) (Table 1). Although statistically significant, the number of events prevented per 1000 treated women is typically less than 10%. Table 1 Summary of radiation effects compared with other treatments*   Outcomes   Treatment  Breast cancer mortality  Overall mortality  All events  Lumpectomy + radiation + tamoxifen vs lumpectomy + radiation  1 study (4)  1 study (4)  1 study (4)  N = 1804  N = 1804  N = 1798  Effect: 0.50 (0.17 to 1.46) NS  Effect: 0.95 (0.63 to 1.44) NS  Effect: 0.76 (0.63 to 0.91)  Evidence: L  Evidence: L  Evidence: L  Lumpectomy + radiation vs lumpectomy  4 studies (2–5)  4 studies (2–5)  2 studies (2,4)  N = 4678  N = 678  N = 1823  Effect: 1.09 (0.67 to 1.79) NS  Effect: 0.96 (0.77 to 1.20) NS  Effect: 0.71(0.62 to 0.82)  Evidence: H  Evidence: H  Evidence: M  1 study (6)      N = 706  Effect: 7.73 (0.90 to 66.50) NS  Evidence: L  Lumpectomy + radiation or Lumpectomy + radiation + tamoxifen vs lumpectomy or lumpectomy + tamoxifen  1 study (7)      N = 1103  Effect: 0.20 (0.04 to 0.88)  Evidence: L  Lumpectomy + radiation vs lumpectomy + tamoxifen      1 study (8)  N = 3409  Effect: 0.32 (0.24 to 0.44)  Evidence: L    Outcomes   Treatment  Breast cancer mortality  Overall mortality  All events  Lumpectomy + radiation + tamoxifen vs lumpectomy + radiation  1 study (4)  1 study (4)  1 study (4)  N = 1804  N = 1804  N = 1798  Effect: 0.50 (0.17 to 1.46) NS  Effect: 0.95 (0.63 to 1.44) NS  Effect: 0.76 (0.63 to 0.91)  Evidence: L  Evidence: L  Evidence: L  Lumpectomy + radiation vs lumpectomy  4 studies (2–5)  4 studies (2–5)  2 studies (2,4)  N = 4678  N = 678  N = 1823  Effect: 1.09 (0.67 to 1.79) NS  Effect: 0.96 (0.77 to 1.20) NS  Effect: 0.71(0.62 to 0.82)  Evidence: H  Evidence: H  Evidence: M  1 study (6)      N = 706  Effect: 7.73 (0.90 to 66.50) NS  Evidence: L  Lumpectomy + radiation or Lumpectomy + radiation + tamoxifen vs lumpectomy or lumpectomy + tamoxifen  1 study (7)      N = 1103  Effect: 0.20 (0.04 to 0.88)  Evidence: L  Lumpectomy + radiation vs lumpectomy + tamoxifen      1 study (8)  N = 3409  Effect: 0.32 (0.24 to 0.44)  Evidence: L  * NS = not significant. Bold = significant at 95% confidence interval. Level of evidence: L = low; M = moderate; H = high. View Large Two randomized controlled trials (2,5) found that while RT had a significant effect on women with negative but not positive margins, the adverse prognostic effect of positive margins remained after RT. Despite similar effectiveness of RT regardless of tumor size, RT did not completely eliminate the increased risk associated with larger vs smaller tumors (3,5). Multiple observational studies report lower rates of local DCIS or invasive cancer for women undergoing BCS + RT over BCS alone, though not all report statistically significant patterns. Observational data show a lack of mortality benefit associated with BCS + RT compared with BCS alone, whereas a single study did find women receiving RT had lower all-cause mortality (9). While generally low level, there is no evidence from observational studies that BCS plus radiation is more or less effective than BCS without radiation in the presence or absence of adverse prognostic factors. This lack of differential effect can be seen for the most important prognostic factors, including grade, tumor size, involved margins, and comedo necrosis. Mastectomy While not studied in a randomized fashion, several observational studies comparing outcomes between mastectomy and BCS or BCS + RT found that women undergoing mastectomy were less likely than women undergoing lumpectomy with or without radiation to experience local DCIS or invasive recurrence. Women undergoing BCS alone were also more likely to experience a local recurrence, primarily because those who had a mastectomy are not at risk for ipsilateral recurrence. We found no study showing a mortality reduction associated with mastectomy over BCS with or without radiation. Low statistical power may account for this apparent lack of benefit. Because the breast cancer mortality after DCIS diagnosis is so low, it is possible that few studies have included sufficient numbers of cases to support identification of a mortality benefit. Selection bias may also contribute to the apparent lack of benefit for mastectomy in observational studies. Clinically larger, multicentric, and more problematic tumors will be more likely to be treated with mastectomy than with BCS. These tumors are also more likely to recur and are more often associated with breast cancer mortality. Thus, equal mortality in spite of differences in severity may be masking a clinically superior treatment. The generally low level of mastectomy compared with BCS plus radiation does not appear to differ in the presence or absence of adverse prognostic factors, including grade, tumor size, involved margins, and comedo necrosis. Tamoxifen In randomized studies, tamoxifen use reduced the risk of recurrent DCIS or invasive carcinoma (4,10) (Table 2). Tamoxifen was associated with a 44% reduction in contralateral disease (relative risk 0.56, 95% confidence interval 0.34 to 0.90) (4) but had no impact on breast cancer and all-cause mortality. Adverse events associated with tamoxifen are consistent with its profile in other settings. There was an increase in hot flushes, fluid retention, and vaginal discharge associated with chemotherapy. Combined treatment (lumpectomy, radiation, and tamoxifen) compared with lumpectomy and tamoxifen reduced the rates of all cancer events by 24% (relative risk 0.76, 95% confidence interval 0.63 to 0.91) (4). There was no differential impact of tamoxifen for women with or without adverse pathological characteristics except for a nonsignificant indication that tamoxifen was less effective for women without comedo necrosis or with smaller tumors. The absolute benefit of tamoxifen for DCIS in reducing recurrence rates after BCS + RT is modest, only about 2%–4%. Table 2 Effect of tamoxifen on patient outcomes (results from randomized controlled trials)* First author, year (reference)  Treatment comparisons  Outcomes  Relative risk (95% CI)  Absolute risk difference (95% CI)  NNT  Attributable/1000 treated  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LRT vs LR  Local invasive carcinoma  1.44 (0.51 to 4.11)  0.01 (−0.02 to 0.04)  NS  NS  Local DCIS recurrence  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive  1.28 (0.58 to 2.81)  0.01 (−0.02 to 0.05)  NS  NS  Total DCIS  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive or DCIS  1.08 (0.60 to 1.97)  0.01 (−0.04 to 0.05)  NS  NS  Fisher, 2001 (4); United States; N = 1804; FU = 83 mo  LRT vs LR  All events  0.76(0.63 to 0.91)  −0.06(−0.09 to −0.02)  18  56  Total invasive or DCIS  0.65(0.52 to 0.83)  −0.06(−0.09 to −0.03)  17  59  Total invasive  0.57(0.41 to 0.80)  −0.04(−0.07 to −0.02)  24  41  Total DCIS  0.76 (0.53 to 1.08)  −0.02 (−0.04 to 0.00)  NS  NS  Local, regional, and distant invasive  0.38 (0.10 to 1.41)  −0.01 (−0.01 to 0.00)  NS  NS  All contralateral diseases  0.56(0.34 to 0.90)  −0.02 (−0.04 to 0.00)  45  22  Contralateral DCIS  0.33(0.12 to 0.91)  −0.01 (−0.02 to 0.00)  90  11  Contralateral invasive  0.67 (0.38 to 1.17)  −0.01 (−0.03 to 0.00)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72(0.54 to 0.96)  −0.03 (−0.06 to 0.00)  32  31  Local DCIS recurrence  0.88 (0.60 to 1.30)  −0.01 (−0.03 to 0.01)  NS  NS  Local invasive carcinoma  0.55(0.35 to 0.87)  −0.02(−0.04 to −0.01)  41  24  Total mortality  0.95 (0.63 to 1.44)  0.00 (−0.02 to 0.02)  NS  NS  Breast cancer mortality  0.50 (0.17 to 1.46)  −0.01 (−0.01 to 0.00)  NS  NS  Death, no evidence of disease  1.00 (0.53 to 1.88)  0.00 (−0.01 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.49 to 1.07)  −0.05 (−0.10 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.47 to 1.09)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.79 (0.55 to 1.14)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.60(0.38 to 0.96)  −0.07(−0.14 to −0.01)  14  71  Local DCIS or invasive carcinoma recurrence  0.72 (0.45 to 1.16)  −0.02 (−0.06 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.75 (0.52 to 1.09)  −0.03 (−0.08 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.58(0.41 to 0.82)  −0.04(−0.07 to −0.02)  22  45  Local DCIS or invasive carcinoma recurrence  1.17 (0.69 to 2.00)  0.02 (−0.06 to 0.10)  NS  NS  Regional nodes recurrence  1.00 (0.20 to 4.95)  0.00 (−0.01 to 0.01)  NS  NS  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LT vs L  Local invasive carcinoma  1.30 (0.81 to 2.08)  0.02 (−0.01 to 0.05)  NS  NS  Local DCIS recurrence  0.75 (0.53 to 1.06)  −0.03 (−0.07 to 0.01)  NS  NS  Total invasive  1.10 (0.72 to 1.67)  0.01 (−0.03 to 0.04)  NS  NS  Total DCIS  0.69(0.50 to 0.97)  −0.04 (−0.08 to 0.00)  23  44  Total invasive or DCIS  0.82 (0.64 to 1.04)  −0.04 (−0.09 to 0.01)  NS  NS  LT or LRT vs L or LR  Local DCIS or invasive carcinoma recurrence  0.88 (0.69 to 1.13)  −0.02 (−0.05 to 0.02)  NS  NS  Local DCIS recurrence  0.73 (0.53 to 1.01)  −0.03 (−0.05 to 0.00)  NS  NS  Local invasive carcinoma  1.27 (0.82 to 1.95)  0.01 (−0.01 to 0.03)  NS  NS  All contralateral diseases  0.52 (0.25 to 1.06)  −0.01 (−0.03 to 0.00)  NS  NS  Contralateral invasive  0.66 (0.30 to 1.45)  −0.01 (−0.02 to 0.01)  NS  NS  Total invasive  1.08 (0.75 to 1.57)  0.01 (−0.02 to 0.03)  NS  NS  Total DCIS  0.68(0.49 to 0.94)  −0.03(−0.06 to −0.01)  29  34  Total invasive or DCIS  0.82 (0.65 to 1.03)  −0.03 (−0.07 to 0.00)  NS  NS  Total invasive or DCIS  0.62 (0.30 to 1.28)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.52 (0.23 to 1.20)    NA  NA  Total invasive or DCIS  0.85 (0.65 to 1.11)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.95 (0.71 to 1.26)    NA  NA  First author, year (reference)  Treatment comparisons  Outcomes  Relative risk (95% CI)  Absolute risk difference (95% CI)  NNT  Attributable/1000 treated  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LRT vs LR  Local invasive carcinoma  1.44 (0.51 to 4.11)  0.01 (−0.02 to 0.04)  NS  NS  Local DCIS recurrence  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive  1.28 (0.58 to 2.81)  0.01 (−0.02 to 0.05)  NS  NS  Total DCIS  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive or DCIS  1.08 (0.60 to 1.97)  0.01 (−0.04 to 0.05)  NS  NS  Fisher, 2001 (4); United States; N = 1804; FU = 83 mo  LRT vs LR  All events  0.76(0.63 to 0.91)  −0.06(−0.09 to −0.02)  18  56  Total invasive or DCIS  0.65(0.52 to 0.83)  −0.06(−0.09 to −0.03)  17  59  Total invasive  0.57(0.41 to 0.80)  −0.04(−0.07 to −0.02)  24  41  Total DCIS  0.76 (0.53 to 1.08)  −0.02 (−0.04 to 0.00)  NS  NS  Local, regional, and distant invasive  0.38 (0.10 to 1.41)  −0.01 (−0.01 to 0.00)  NS  NS  All contralateral diseases  0.56(0.34 to 0.90)  −0.02 (−0.04 to 0.00)  45  22  Contralateral DCIS  0.33(0.12 to 0.91)  −0.01 (−0.02 to 0.00)  90  11  Contralateral invasive  0.67 (0.38 to 1.17)  −0.01 (−0.03 to 0.00)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72(0.54 to 0.96)  −0.03 (−0.06 to 0.00)  32  31  Local DCIS recurrence  0.88 (0.60 to 1.30)  −0.01 (−0.03 to 0.01)  NS  NS  Local invasive carcinoma  0.55(0.35 to 0.87)  −0.02(−0.04 to −0.01)  41  24  Total mortality  0.95 (0.63 to 1.44)  0.00 (−0.02 to 0.02)  NS  NS  Breast cancer mortality  0.50 (0.17 to 1.46)  −0.01 (−0.01 to 0.00)  NS  NS  Death, no evidence of disease  1.00 (0.53 to 1.88)  0.00 (−0.01 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.49 to 1.07)  −0.05 (−0.10 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.47 to 1.09)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.79 (0.55 to 1.14)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.60(0.38 to 0.96)  −0.07(−0.14 to −0.01)  14  71  Local DCIS or invasive carcinoma recurrence  0.72 (0.45 to 1.16)  −0.02 (−0.06 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.75 (0.52 to 1.09)  −0.03 (−0.08 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.58(0.41 to 0.82)  −0.04(−0.07 to −0.02)  22  45  Local DCIS or invasive carcinoma recurrence  1.17 (0.69 to 2.00)  0.02 (−0.06 to 0.10)  NS  NS  Regional nodes recurrence  1.00 (0.20 to 4.95)  0.00 (−0.01 to 0.01)  NS  NS  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LT vs L  Local invasive carcinoma  1.30 (0.81 to 2.08)  0.02 (−0.01 to 0.05)  NS  NS  Local DCIS recurrence  0.75 (0.53 to 1.06)  −0.03 (−0.07 to 0.01)  NS  NS  Total invasive  1.10 (0.72 to 1.67)  0.01 (−0.03 to 0.04)  NS  NS  Total DCIS  0.69(0.50 to 0.97)  −0.04 (−0.08 to 0.00)  23  44  Total invasive or DCIS  0.82 (0.64 to 1.04)  −0.04 (−0.09 to 0.01)  NS  NS  LT or LRT vs L or LR  Local DCIS or invasive carcinoma recurrence  0.88 (0.69 to 1.13)  −0.02 (−0.05 to 0.02)  NS  NS  Local DCIS recurrence  0.73 (0.53 to 1.01)  −0.03 (−0.05 to 0.00)  NS  NS  Local invasive carcinoma  1.27 (0.82 to 1.95)  0.01 (−0.01 to 0.03)  NS  NS  All contralateral diseases  0.52 (0.25 to 1.06)  −0.01 (−0.03 to 0.00)  NS  NS  Contralateral invasive  0.66 (0.30 to 1.45)  −0.01 (−0.02 to 0.01)  NS  NS  Total invasive  1.08 (0.75 to 1.57)  0.01 (−0.02 to 0.03)  NS  NS  Total DCIS  0.68(0.49 to 0.94)  −0.03(−0.06 to −0.01)  29  34  Total invasive or DCIS  0.82 (0.65 to 1.03)  −0.03 (−0.07 to 0.00)  NS  NS  Total invasive or DCIS  0.62 (0.30 to 1.28)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.52 (0.23 to 1.20)    NA  NA  Total invasive or DCIS  0.85 (0.65 to 1.11)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.95 (0.71 to 1.26)    NA  NA  * CI = confidence interval; DCIS = ductal carcinoma in situ; FU = follow-up; L = lumpectomy; N = number; NA = not applicable; NNT = number needed to treat to have one event; NS = not significant; R = radiation; T = tamoxifen. Bold values are significant at 95% confidence interval and related calculations. View Large The only observational study of tamoxifen use after DCIS that included comparisons with nonusers found that women with DCIS who received tamoxifen had the same hazard of local DCIS or invasive cancer as women who did not receive tamoxifen (7). Several ongoing studies are evaluating the effects of aromatase inhibition therapy or selective estrogen receptor modulators (NCT00072462, NCT00077168, NCT00290745, NCT00053898, and NCT00004247). The effects of adjuvant chemotherapy with fulvestrant or tamoxifen on women with DCIS who are undergoing surgery treatment will be reported after two ongoing studies (NCT00126464 and NCT00183963). The effects of EGFR-ErbB-2 inhibitors have never been reported in women with DCIS. One ongoing study is examining the effects of lapatinib in women with DCIS. Neoadjuvant therapy with HER2 antibody has never been published in women with DCIS. Two ongoing studies are testing the effects of neoadjuvant Herceptin or trastuzumab in women with DCIS (NCT00496808 and NCT00769379). Ongoing studies aim to investigate several agents that have never been administered in women with DCIS. Vorinostat, which inhibits histone deacetylase 1 and 3, is being tested (NCT00788112). One study is testing the effects of intraductal carboplatin, organoplatinum compound, in women with DCIS (NCT00669747). Adjuvant therapy of protein kinase inhibitor, gefitinib, is being examined in another ongoing trial (NCT00082667). Accelerated Partial Breast Irradiation An emerging controversy is whether accelerated partial breast irradiation (APBI) therapy is as effective as whole-breast RT. Observational studies reporting results of APBI for DCIS are limited to the MammoSite technology and do not include control groups (11–13). The ongoing NSABP-39 trial randomizes women to whole or APBI therapy. For that trial, three partial breast techniques are treated as equivalent: multicatheter brachytherapy, MammoSite balloon catheter, and 3D conformational external-beam radiation. Other ongoing trials comparing whole breast to specific types of APBI include those being conducted by the Ontario Clinical Oncology Group (NCT00282035) and Stanford University (NCT00185744). Summary Randomized trials provide consistent evidence that DCIS treated with breast-conserving therapy plus radiation compared with breast-conserving therapy alone results in reduced total local recurrence by 53% and local invasive breast cancer recurrence by 46% with no differences in overall and breast cancer mortality, all or invasive contralateral breast cancer, total distant, or local regional nodes recurrence. Observational studies point to somewhat inconsistent effects regarding the benefit of BCS with RT relative to BCS alone. The observational studies, however, are frequently underpowered, subject to selection bias (that is, patients are not randomly allocated to RT or not) and inconsistent in their control of known confounding factors. While not studied in a randomized fashion, studies point to equivalent outcomes between BCS plus radiation and mastectomy, whereas BCS alone tends to be inferior to mastectomy. Subset analyses of randomized controlled trials, while generally lower level of evidence [eg, not always multivariate adjusted (2,3,5,14)], do not point to differential effectiveness of surgery vs radiation in the presence of some adverse prognostic factors, including multifocality, marked lymphoid infiltrate, marked stroma, slight necrosis, or medium tumor size. This lack of differential effect suggests that treatment alone may not eliminate the adverse prognosis but also suggests that for patients with adverse prognostic features, treatment may be particularly important. Evidence of the effectiveness of tamoxifen for treating DCIS is based on a very small number of randomized and observational studies but is quite promising. Although the relative benefit of tamoxifen is about 30%–50%, the absolute reduction is only about 2%–4%, which may not justify 5 years of endocrine treatment. The role of systemic treatments of DCIS needs further investigation. Future research should be designed to examine treatment effects among subgroups of women with different levels of baseline risk factors for breast cancer, for example, BRCA mutation carriers, and different predictors of poor outcomes, for example, large comedo tumors. Individualized therapy should be possible when future randomized controlled trials would be designed to detect differences in outcomes in patient subpopulations. Synthesizing across studies, we found no effects on overall mortality or breast cancer mortality. Only one observational study reported significant reduction in crude odds of breast cancer mortality after adjuvant radiotherapy. All cancer events were reduced after combined treatment (lumpectomy plus radiotherapy and chemotherapy) when compared with dual therapy (lumpectomy plus radiotherapy or lumpectomy plus tamoxifen). However, given the low level of mortality associated with DCIS and the long treatment horizon, it is likely that even the largest of these studies is underpowered to identify a mortality benefit. A similar conclusion was reached with invasive breast cancer where mortality is much more common (15). Yet, until all studies were pooled using meta-analysis, no mortality effect was observed when comparing BCS + RT with BCS alone. The overall evidence of treatment effectiveness is consistent with treatment effectiveness for invasive breast cancer. This insight should facilitate transfer of knowledge about treatment effectiveness from invasive breast cancer to DCIS. 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The Impact of Surgery, Radiation, and Systemic Treatment on Outcomes in Patients With Ductal Carcinoma In Situ

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Oxford University Press
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© The Author 2010. Published by Oxford University Press.
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1052-6773
eISSN
1745-6614
DOI
10.1093/jncimonographs/lgq022
pmid
20956816
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Abstract

Abstract Background Ductal carcinoma in situ (DCIS) is associated with low rates of mortality. Outcomes are generally assessed in terms of recurrence. Methods Published studies were abstracted from MEDLINE and other sources. We include articles published through January 31, 2009; 10 publications of five randomized controlled trials and 133 publications of 64 observational studies were reviewed. Results Whole-breast radiation therapy following breast-conserving surgery (BCS) was consistently associated with a reduced incidence of local DCIS recurrence and local invasive carcinoma. Women undergoing mastectomy were less likely than women undergoing lumpectomy with or without radiation to experience local DCIS or invasive recurrence. Tamoxifen use reduced risk of recurrent DCIS or invasive carcinoma. Conclusions BCS plus radiation and mastectomy appear to yield equivalent outcomes, whereas BCS alone tends to be inferior to mastectomy. Tamoxifen seems helpful in treating DCIS. Background Because ductal carcinoma in situ (DCIS) is associated with low rates of mortality, analyses of the success of treatment must focus on recurrence. The basic treatment decisions reflect those for invasive breast cancer: mastectomy and breast-conserving surgery (BCS) with or without radiation. Chemotherapy is not in the repertoire. However, adjuvant therapy with tamoxifen is. Methods We used the methods described in detail by Virnig (1). We identified 10 publications from five randomized controlled trials and 133 reports from observational studies that were published from 1965 through January 31, 2009. This article includes a highly abbreviated reference list. Results The most consistently measured outcomes were ipsilateral DCIS, ipsilateral invasive cancer, combined ipsilateral DCIS and invasive cancer, contralateral DCIS, contralateral invasive cancer, combined contralateral DCIS and invasive cancer, breast cancer mortality, all-cause mortality, chemotherapy use, local recurrence, regional recurrence, distant recurrence, and other outcomes. For the purposes of this report, we consider BCS, lumpectomy, and wide local excision to be analogous terms. BCS With Radiation In several randomized trials, whole-breast radiation therapy (RT) following BCS was consistently associated with a reduced incidence of local DCIS recurrence and local invasive carcinoma but with no impact on breast cancer mortality or total mortality (2–4) (Table 1). Although statistically significant, the number of events prevented per 1000 treated women is typically less than 10%. Table 1 Summary of radiation effects compared with other treatments*   Outcomes   Treatment  Breast cancer mortality  Overall mortality  All events  Lumpectomy + radiation + tamoxifen vs lumpectomy + radiation  1 study (4)  1 study (4)  1 study (4)  N = 1804  N = 1804  N = 1798  Effect: 0.50 (0.17 to 1.46) NS  Effect: 0.95 (0.63 to 1.44) NS  Effect: 0.76 (0.63 to 0.91)  Evidence: L  Evidence: L  Evidence: L  Lumpectomy + radiation vs lumpectomy  4 studies (2–5)  4 studies (2–5)  2 studies (2,4)  N = 4678  N = 678  N = 1823  Effect: 1.09 (0.67 to 1.79) NS  Effect: 0.96 (0.77 to 1.20) NS  Effect: 0.71(0.62 to 0.82)  Evidence: H  Evidence: H  Evidence: M  1 study (6)      N = 706  Effect: 7.73 (0.90 to 66.50) NS  Evidence: L  Lumpectomy + radiation or Lumpectomy + radiation + tamoxifen vs lumpectomy or lumpectomy + tamoxifen  1 study (7)      N = 1103  Effect: 0.20 (0.04 to 0.88)  Evidence: L  Lumpectomy + radiation vs lumpectomy + tamoxifen      1 study (8)  N = 3409  Effect: 0.32 (0.24 to 0.44)  Evidence: L    Outcomes   Treatment  Breast cancer mortality  Overall mortality  All events  Lumpectomy + radiation + tamoxifen vs lumpectomy + radiation  1 study (4)  1 study (4)  1 study (4)  N = 1804  N = 1804  N = 1798  Effect: 0.50 (0.17 to 1.46) NS  Effect: 0.95 (0.63 to 1.44) NS  Effect: 0.76 (0.63 to 0.91)  Evidence: L  Evidence: L  Evidence: L  Lumpectomy + radiation vs lumpectomy  4 studies (2–5)  4 studies (2–5)  2 studies (2,4)  N = 4678  N = 678  N = 1823  Effect: 1.09 (0.67 to 1.79) NS  Effect: 0.96 (0.77 to 1.20) NS  Effect: 0.71(0.62 to 0.82)  Evidence: H  Evidence: H  Evidence: M  1 study (6)      N = 706  Effect: 7.73 (0.90 to 66.50) NS  Evidence: L  Lumpectomy + radiation or Lumpectomy + radiation + tamoxifen vs lumpectomy or lumpectomy + tamoxifen  1 study (7)      N = 1103  Effect: 0.20 (0.04 to 0.88)  Evidence: L  Lumpectomy + radiation vs lumpectomy + tamoxifen      1 study (8)  N = 3409  Effect: 0.32 (0.24 to 0.44)  Evidence: L  * NS = not significant. Bold = significant at 95% confidence interval. Level of evidence: L = low; M = moderate; H = high. View Large Two randomized controlled trials (2,5) found that while RT had a significant effect on women with negative but not positive margins, the adverse prognostic effect of positive margins remained after RT. Despite similar effectiveness of RT regardless of tumor size, RT did not completely eliminate the increased risk associated with larger vs smaller tumors (3,5). Multiple observational studies report lower rates of local DCIS or invasive cancer for women undergoing BCS + RT over BCS alone, though not all report statistically significant patterns. Observational data show a lack of mortality benefit associated with BCS + RT compared with BCS alone, whereas a single study did find women receiving RT had lower all-cause mortality (9). While generally low level, there is no evidence from observational studies that BCS plus radiation is more or less effective than BCS without radiation in the presence or absence of adverse prognostic factors. This lack of differential effect can be seen for the most important prognostic factors, including grade, tumor size, involved margins, and comedo necrosis. Mastectomy While not studied in a randomized fashion, several observational studies comparing outcomes between mastectomy and BCS or BCS + RT found that women undergoing mastectomy were less likely than women undergoing lumpectomy with or without radiation to experience local DCIS or invasive recurrence. Women undergoing BCS alone were also more likely to experience a local recurrence, primarily because those who had a mastectomy are not at risk for ipsilateral recurrence. We found no study showing a mortality reduction associated with mastectomy over BCS with or without radiation. Low statistical power may account for this apparent lack of benefit. Because the breast cancer mortality after DCIS diagnosis is so low, it is possible that few studies have included sufficient numbers of cases to support identification of a mortality benefit. Selection bias may also contribute to the apparent lack of benefit for mastectomy in observational studies. Clinically larger, multicentric, and more problematic tumors will be more likely to be treated with mastectomy than with BCS. These tumors are also more likely to recur and are more often associated with breast cancer mortality. Thus, equal mortality in spite of differences in severity may be masking a clinically superior treatment. The generally low level of mastectomy compared with BCS plus radiation does not appear to differ in the presence or absence of adverse prognostic factors, including grade, tumor size, involved margins, and comedo necrosis. Tamoxifen In randomized studies, tamoxifen use reduced the risk of recurrent DCIS or invasive carcinoma (4,10) (Table 2). Tamoxifen was associated with a 44% reduction in contralateral disease (relative risk 0.56, 95% confidence interval 0.34 to 0.90) (4) but had no impact on breast cancer and all-cause mortality. Adverse events associated with tamoxifen are consistent with its profile in other settings. There was an increase in hot flushes, fluid retention, and vaginal discharge associated with chemotherapy. Combined treatment (lumpectomy, radiation, and tamoxifen) compared with lumpectomy and tamoxifen reduced the rates of all cancer events by 24% (relative risk 0.76, 95% confidence interval 0.63 to 0.91) (4). There was no differential impact of tamoxifen for women with or without adverse pathological characteristics except for a nonsignificant indication that tamoxifen was less effective for women without comedo necrosis or with smaller tumors. The absolute benefit of tamoxifen for DCIS in reducing recurrence rates after BCS + RT is modest, only about 2%–4%. Table 2 Effect of tamoxifen on patient outcomes (results from randomized controlled trials)* First author, year (reference)  Treatment comparisons  Outcomes  Relative risk (95% CI)  Absolute risk difference (95% CI)  NNT  Attributable/1000 treated  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LRT vs LR  Local invasive carcinoma  1.44 (0.51 to 4.11)  0.01 (−0.02 to 0.04)  NS  NS  Local DCIS recurrence  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive  1.28 (0.58 to 2.81)  0.01 (−0.02 to 0.05)  NS  NS  Total DCIS  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive or DCIS  1.08 (0.60 to 1.97)  0.01 (−0.04 to 0.05)  NS  NS  Fisher, 2001 (4); United States; N = 1804; FU = 83 mo  LRT vs LR  All events  0.76(0.63 to 0.91)  −0.06(−0.09 to −0.02)  18  56  Total invasive or DCIS  0.65(0.52 to 0.83)  −0.06(−0.09 to −0.03)  17  59  Total invasive  0.57(0.41 to 0.80)  −0.04(−0.07 to −0.02)  24  41  Total DCIS  0.76 (0.53 to 1.08)  −0.02 (−0.04 to 0.00)  NS  NS  Local, regional, and distant invasive  0.38 (0.10 to 1.41)  −0.01 (−0.01 to 0.00)  NS  NS  All contralateral diseases  0.56(0.34 to 0.90)  −0.02 (−0.04 to 0.00)  45  22  Contralateral DCIS  0.33(0.12 to 0.91)  −0.01 (−0.02 to 0.00)  90  11  Contralateral invasive  0.67 (0.38 to 1.17)  −0.01 (−0.03 to 0.00)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72(0.54 to 0.96)  −0.03 (−0.06 to 0.00)  32  31  Local DCIS recurrence  0.88 (0.60 to 1.30)  −0.01 (−0.03 to 0.01)  NS  NS  Local invasive carcinoma  0.55(0.35 to 0.87)  −0.02(−0.04 to −0.01)  41  24  Total mortality  0.95 (0.63 to 1.44)  0.00 (−0.02 to 0.02)  NS  NS  Breast cancer mortality  0.50 (0.17 to 1.46)  −0.01 (−0.01 to 0.00)  NS  NS  Death, no evidence of disease  1.00 (0.53 to 1.88)  0.00 (−0.01 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.49 to 1.07)  −0.05 (−0.10 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.47 to 1.09)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.79 (0.55 to 1.14)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.60(0.38 to 0.96)  −0.07(−0.14 to −0.01)  14  71  Local DCIS or invasive carcinoma recurrence  0.72 (0.45 to 1.16)  −0.02 (−0.06 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.75 (0.52 to 1.09)  −0.03 (−0.08 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.58(0.41 to 0.82)  −0.04(−0.07 to −0.02)  22  45  Local DCIS or invasive carcinoma recurrence  1.17 (0.69 to 2.00)  0.02 (−0.06 to 0.10)  NS  NS  Regional nodes recurrence  1.00 (0.20 to 4.95)  0.00 (−0.01 to 0.01)  NS  NS  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LT vs L  Local invasive carcinoma  1.30 (0.81 to 2.08)  0.02 (−0.01 to 0.05)  NS  NS  Local DCIS recurrence  0.75 (0.53 to 1.06)  −0.03 (−0.07 to 0.01)  NS  NS  Total invasive  1.10 (0.72 to 1.67)  0.01 (−0.03 to 0.04)  NS  NS  Total DCIS  0.69(0.50 to 0.97)  −0.04 (−0.08 to 0.00)  23  44  Total invasive or DCIS  0.82 (0.64 to 1.04)  −0.04 (−0.09 to 0.01)  NS  NS  LT or LRT vs L or LR  Local DCIS or invasive carcinoma recurrence  0.88 (0.69 to 1.13)  −0.02 (−0.05 to 0.02)  NS  NS  Local DCIS recurrence  0.73 (0.53 to 1.01)  −0.03 (−0.05 to 0.00)  NS  NS  Local invasive carcinoma  1.27 (0.82 to 1.95)  0.01 (−0.01 to 0.03)  NS  NS  All contralateral diseases  0.52 (0.25 to 1.06)  −0.01 (−0.03 to 0.00)  NS  NS  Contralateral invasive  0.66 (0.30 to 1.45)  −0.01 (−0.02 to 0.01)  NS  NS  Total invasive  1.08 (0.75 to 1.57)  0.01 (−0.02 to 0.03)  NS  NS  Total DCIS  0.68(0.49 to 0.94)  −0.03(−0.06 to −0.01)  29  34  Total invasive or DCIS  0.82 (0.65 to 1.03)  −0.03 (−0.07 to 0.00)  NS  NS  Total invasive or DCIS  0.62 (0.30 to 1.28)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.52 (0.23 to 1.20)    NA  NA  Total invasive or DCIS  0.85 (0.65 to 1.11)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.95 (0.71 to 1.26)    NA  NA  First author, year (reference)  Treatment comparisons  Outcomes  Relative risk (95% CI)  Absolute risk difference (95% CI)  NNT  Attributable/1000 treated  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LRT vs LR  Local invasive carcinoma  1.44 (0.51 to 4.11)  0.01 (−0.02 to 0.04)  NS  NS  Local DCIS recurrence  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive  1.28 (0.58 to 2.81)  0.01 (−0.02 to 0.05)  NS  NS  Total DCIS  0.84 (0.32 to 2.23)  −0.01 (−0.03 to 0.02)  NS  NS  Total invasive or DCIS  1.08 (0.60 to 1.97)  0.01 (−0.04 to 0.05)  NS  NS  Fisher, 2001 (4); United States; N = 1804; FU = 83 mo  LRT vs LR  All events  0.76(0.63 to 0.91)  −0.06(−0.09 to −0.02)  18  56  Total invasive or DCIS  0.65(0.52 to 0.83)  −0.06(−0.09 to −0.03)  17  59  Total invasive  0.57(0.41 to 0.80)  −0.04(−0.07 to −0.02)  24  41  Total DCIS  0.76 (0.53 to 1.08)  −0.02 (−0.04 to 0.00)  NS  NS  Local, regional, and distant invasive  0.38 (0.10 to 1.41)  −0.01 (−0.01 to 0.00)  NS  NS  All contralateral diseases  0.56(0.34 to 0.90)  −0.02 (−0.04 to 0.00)  45  22  Contralateral DCIS  0.33(0.12 to 0.91)  −0.01 (−0.02 to 0.00)  90  11  Contralateral invasive  0.67 (0.38 to 1.17)  −0.01 (−0.03 to 0.00)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72(0.54 to 0.96)  −0.03 (−0.06 to 0.00)  32  31  Local DCIS recurrence  0.88 (0.60 to 1.30)  −0.01 (−0.03 to 0.01)  NS  NS  Local invasive carcinoma  0.55(0.35 to 0.87)  −0.02(−0.04 to −0.01)  41  24  Total mortality  0.95 (0.63 to 1.44)  0.00 (−0.02 to 0.02)  NS  NS  Breast cancer mortality  0.50 (0.17 to 1.46)  −0.01 (−0.01 to 0.00)  NS  NS  Death, no evidence of disease  1.00 (0.53 to 1.88)  0.00 (−0.01 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.49 to 1.07)  −0.05 (−0.10 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.72 (0.47 to 1.09)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.79 (0.55 to 1.14)  −0.02 (−0.05 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.60(0.38 to 0.96)  −0.07(−0.14 to −0.01)  14  71  Local DCIS or invasive carcinoma recurrence  0.72 (0.45 to 1.16)  −0.02 (−0.06 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.75 (0.52 to 1.09)  −0.03 (−0.08 to 0.01)  NS  NS  Local DCIS or invasive carcinoma recurrence  0.58(0.41 to 0.82)  −0.04(−0.07 to −0.02)  22  45  Local DCIS or invasive carcinoma recurrence  1.17 (0.69 to 2.00)  0.02 (−0.06 to 0.10)  NS  NS  Regional nodes recurrence  1.00 (0.20 to 4.95)  0.00 (−0.01 to 0.01)  NS  NS  Houghton, 2003 (10); United Kingdom, Australia, New Zealand; N = 1694; FU = 52.6 mo  LT vs L  Local invasive carcinoma  1.30 (0.81 to 2.08)  0.02 (−0.01 to 0.05)  NS  NS  Local DCIS recurrence  0.75 (0.53 to 1.06)  −0.03 (−0.07 to 0.01)  NS  NS  Total invasive  1.10 (0.72 to 1.67)  0.01 (−0.03 to 0.04)  NS  NS  Total DCIS  0.69(0.50 to 0.97)  −0.04 (−0.08 to 0.00)  23  44  Total invasive or DCIS  0.82 (0.64 to 1.04)  −0.04 (−0.09 to 0.01)  NS  NS  LT or LRT vs L or LR  Local DCIS or invasive carcinoma recurrence  0.88 (0.69 to 1.13)  −0.02 (−0.05 to 0.02)  NS  NS  Local DCIS recurrence  0.73 (0.53 to 1.01)  −0.03 (−0.05 to 0.00)  NS  NS  Local invasive carcinoma  1.27 (0.82 to 1.95)  0.01 (−0.01 to 0.03)  NS  NS  All contralateral diseases  0.52 (0.25 to 1.06)  −0.01 (−0.03 to 0.00)  NS  NS  Contralateral invasive  0.66 (0.30 to 1.45)  −0.01 (−0.02 to 0.01)  NS  NS  Total invasive  1.08 (0.75 to 1.57)  0.01 (−0.02 to 0.03)  NS  NS  Total DCIS  0.68(0.49 to 0.94)  −0.03(−0.06 to −0.01)  29  34  Total invasive or DCIS  0.82 (0.65 to 1.03)  −0.03 (−0.07 to 0.00)  NS  NS  Total invasive or DCIS  0.62 (0.30 to 1.28)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.52 (0.23 to 1.20)    NA  NA  Total invasive or DCIS  0.85 (0.65 to 1.11)    NA  NA  Local DCIS or invasive carcinoma recurrence  0.95 (0.71 to 1.26)    NA  NA  * CI = confidence interval; DCIS = ductal carcinoma in situ; FU = follow-up; L = lumpectomy; N = number; NA = not applicable; NNT = number needed to treat to have one event; NS = not significant; R = radiation; T = tamoxifen. Bold values are significant at 95% confidence interval and related calculations. View Large The only observational study of tamoxifen use after DCIS that included comparisons with nonusers found that women with DCIS who received tamoxifen had the same hazard of local DCIS or invasive cancer as women who did not receive tamoxifen (7). Several ongoing studies are evaluating the effects of aromatase inhibition therapy or selective estrogen receptor modulators (NCT00072462, NCT00077168, NCT00290745, NCT00053898, and NCT00004247). The effects of adjuvant chemotherapy with fulvestrant or tamoxifen on women with DCIS who are undergoing surgery treatment will be reported after two ongoing studies (NCT00126464 and NCT00183963). The effects of EGFR-ErbB-2 inhibitors have never been reported in women with DCIS. One ongoing study is examining the effects of lapatinib in women with DCIS. Neoadjuvant therapy with HER2 antibody has never been published in women with DCIS. Two ongoing studies are testing the effects of neoadjuvant Herceptin or trastuzumab in women with DCIS (NCT00496808 and NCT00769379). Ongoing studies aim to investigate several agents that have never been administered in women with DCIS. Vorinostat, which inhibits histone deacetylase 1 and 3, is being tested (NCT00788112). One study is testing the effects of intraductal carboplatin, organoplatinum compound, in women with DCIS (NCT00669747). Adjuvant therapy of protein kinase inhibitor, gefitinib, is being examined in another ongoing trial (NCT00082667). Accelerated Partial Breast Irradiation An emerging controversy is whether accelerated partial breast irradiation (APBI) therapy is as effective as whole-breast RT. Observational studies reporting results of APBI for DCIS are limited to the MammoSite technology and do not include control groups (11–13). The ongoing NSABP-39 trial randomizes women to whole or APBI therapy. For that trial, three partial breast techniques are treated as equivalent: multicatheter brachytherapy, MammoSite balloon catheter, and 3D conformational external-beam radiation. Other ongoing trials comparing whole breast to specific types of APBI include those being conducted by the Ontario Clinical Oncology Group (NCT00282035) and Stanford University (NCT00185744). Summary Randomized trials provide consistent evidence that DCIS treated with breast-conserving therapy plus radiation compared with breast-conserving therapy alone results in reduced total local recurrence by 53% and local invasive breast cancer recurrence by 46% with no differences in overall and breast cancer mortality, all or invasive contralateral breast cancer, total distant, or local regional nodes recurrence. Observational studies point to somewhat inconsistent effects regarding the benefit of BCS with RT relative to BCS alone. The observational studies, however, are frequently underpowered, subject to selection bias (that is, patients are not randomly allocated to RT or not) and inconsistent in their control of known confounding factors. While not studied in a randomized fashion, studies point to equivalent outcomes between BCS plus radiation and mastectomy, whereas BCS alone tends to be inferior to mastectomy. Subset analyses of randomized controlled trials, while generally lower level of evidence [eg, not always multivariate adjusted (2,3,5,14)], do not point to differential effectiveness of surgery vs radiation in the presence of some adverse prognostic factors, including multifocality, marked lymphoid infiltrate, marked stroma, slight necrosis, or medium tumor size. This lack of differential effect suggests that treatment alone may not eliminate the adverse prognosis but also suggests that for patients with adverse prognostic features, treatment may be particularly important. Evidence of the effectiveness of tamoxifen for treating DCIS is based on a very small number of randomized and observational studies but is quite promising. Although the relative benefit of tamoxifen is about 30%–50%, the absolute reduction is only about 2%–4%, which may not justify 5 years of endocrine treatment. The role of systemic treatments of DCIS needs further investigation. Future research should be designed to examine treatment effects among subgroups of women with different levels of baseline risk factors for breast cancer, for example, BRCA mutation carriers, and different predictors of poor outcomes, for example, large comedo tumors. Individualized therapy should be possible when future randomized controlled trials would be designed to detect differences in outcomes in patient subpopulations. Synthesizing across studies, we found no effects on overall mortality or breast cancer mortality. Only one observational study reported significant reduction in crude odds of breast cancer mortality after adjuvant radiotherapy. All cancer events were reduced after combined treatment (lumpectomy plus radiotherapy and chemotherapy) when compared with dual therapy (lumpectomy plus radiotherapy or lumpectomy plus tamoxifen). However, given the low level of mortality associated with DCIS and the long treatment horizon, it is likely that even the largest of these studies is underpowered to identify a mortality benefit. A similar conclusion was reached with invasive breast cancer where mortality is much more common (15). Yet, until all studies were pooled using meta-analysis, no mortality effect was observed when comparing BCS + RT with BCS alone. The overall evidence of treatment effectiveness is consistent with treatment effectiveness for invasive breast cancer. This insight should facilitate transfer of knowledge about treatment effectiveness from invasive breast cancer to DCIS. 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Journal

JNCI Monographs – Oxford University Press

Published: Oct 1, 2010

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