Document Detail

Radiotherapy after conservative surgery in ductal carcinoma in situ of the breast: a review.
Jump to Full Text
MedLine Citation:
PMID:  22655186     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Several large prospective and retrospective studies have demonstrated excellent long-term outcomes after breast conservative treatment with radiation in invasive breast cancer. Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an accepted management strategy for patients with DCIS. Adding radiation treatment after conservative surgery enables to reduce, without any significant risks, the rate of local recurrence (LR) by approximately 50% in retrospective and randomized clinical trials. As about 50% of LRs are invasive and have a negative psychological impact, minimizing recurrence is important. Local and local-regional recurrences after initial breast conservation treatment with radiation can be salvaged with high rates of survival and freedom from distant metastases.
Authors:
Maurizio Amichetti; Cristiana Vidali
Related Documents :
24467226 - Inhibiting metastatic breast cancer cell migration via the synergy of targeted, ph-trig...
23478736 - Carcinoma of vagina in utero-vaginal prolapse: a rare presentation.
23238816 - Part ii. mitochondrial mutational status of high nitric oxide adapted cell line bt-20 (...
12173666 - Breast carcinoma in patients with dermatomyositis: a retrospective analysis of eight ca...
23269276 - Autoantibody signatures involving glycolysis and splicesome proteins precede a diagnosi...
9392466 - Radiological features of papillary carcinoma of the breast.
Publication Detail:
Type:  Journal Article     Date:  2012-05-13
Journal Detail:
Title:  International journal of surgical oncology     Volume:  2012     ISSN:  2090-1410     ISO Abbreviation:  Int J Surg Oncol     Publication Date:  2012  
Date Detail:
Created Date:  2012-06-01     Completed Date:  2012-08-23     Revised Date:  2013-02-28    
Medline Journal Info:
Nlm Unique ID:  101566285     Medline TA:  Int J Surg Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  635404     Citation Subset:  -    
Affiliation:
ATreP, Agenzia Provinciale per la Protonterapia, Via Perini 181, 38122 Trento, Italy.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Int J Surg Oncol
Journal ID (iso-abbrev): Int J Surg Oncol
Journal ID (publisher-id): IJSO
ISSN: 2090-1402
ISSN: 2090-1410
Publisher: Hindawi Publishing Corporation
Article Information
Download PDF
Copyright © 2012 M. Amichetti and C. Vidali.
open-access:
Received Day: 22 Month: 12 Year: 2011
Accepted Day: 6 Month: 3 Year: 2012
Print publication date: Year: 2012
Electronic publication date: Day: 13 Month: 5 Year: 2012
Volume: 2012E-location ID: 635404
ID: 3359679
PubMed Id: 22655186
DOI: 10.1155/2012/635404

Radiotherapy after Conservative Surgery in Ductal Carcinoma In Situ of the Breast: A Review
Maurizio Amichetti1*
Cristiana Vidali2
1ATreP, Agenzia Provinciale per la Protonterapia, Via Perini 181, 38122 Trento, Italy
2S.C. di Radioterapia, Azienda Ospedaliero-Universitaria, Via della Pietà 19, 34129 Trieste, Italy
Correspondence: *Maurizio Amichetti: amichett@atrep.it
[other] Academic Editor: Bruno Cutuli

1. Introduction

The term ductal carcinoma in situ (DCIS) encompasses a heterogeneous group of lesions with different biological potential and clinical behaviour [1].

There is no consensus regarding how to optimize the treatment for patients with DCIS: mastectomy cures almost all patients, but it is considered an overtreatment in many cases, particularly when they are small mammographic-detected lesions.

Most women are eligible for breast conservative surgery (BCS), a major decision is whether or not radiotherapy (RT) must follow surgical excision in order to control any microscopic residual disease. It is likely that not all patients with DCIS require RT following BCS; it is important to identify patients at high risk of recurrence or progression to invasive breast cancer who can benefit from RT. It is argued that RT should be used selectively, because of possible short- and long-term morbidity, and also because radiation fibrosis may hamper interpretation of follow-up mammograms.

Unfortunately, until now, the ability to select DCIS that is likely to recur or progress to invasive breast cancer is still limited, and there is a lack of level-1 evidence supporting the omission of adjuvant RT in selected low-risk cases, which could potentially be adequately treated by complete local excision.

Patients with DCIS treated with BCS may recur approximately in the same proportion either as DCIS or invasive breast cancer [2]. Efforts have continued to attempt to define the subsets of patients to whom we should offer the different treatment options for local treatment (surgical excision alone or plus radiation or mastectomy). Most of the DCIS patients are interested in breast conservative treatment and consequently a major decision is whether or not to add radiation treatment. Irrespective of whether a low-risk group can be identified, the role of radiation after wide excision of DCIS remains controversial.

The aim of this paper is to report and summarize the indications for RT after BCS and the results of retrospective, prospective randomized studies and meta-analyses on this issue.


2. Retrospective Studies

Published population-based retrospective mono-institutional and collaborative studies have demonstrated excellent long-term outcomes after BCS with RT.

Multiple observational studies report lower rates of recurrence (DCIS or invasive) for patients undergoing BCS + RT over BCS alone. All but one [3] of the observational studies show a lack of mortality benefit associated with BCS + RT compared with BCS alone.

Surveillance, Epidemiology, and End Results data have shown that still a substantial number of patients in the United States are treated with excision alone, without radiation [4].

An international collaborative multi-institutional study conducted by 10 Institutions in Europe and North America involving 1003 patients with mammographically detected DCIS has been published with long-term results [5]. Adjuvant tamoxifen was not used. The median followup was 8.5 years; the 15-year overall survival (OS) was 89%, and the 15-year cause-specific survival (CSS) was 98%.

The rate of any local recurrence (LR) (DCIS plus invasive) was 19%. Significant factors for LR were found to be the final pathologically positive margins and the patient's younger age. For the favorable subgroup of patients aged ≥50 years with negative margins, the 10-year rate of local failure was ≤8%.

A retrospective French collaborative study reported on 882 DCIS treated from 1985 to 1995 [6]. Mastectomy, BCS alone, and BCS + RT were performed, respectively, in 20%, 22%, and 58% of patients. Thus 515 women out of 705, who were treated with BCS, received adjuvant RT; a 10 Gy boost was given to 52% of them. Hormonal therapy was administered to 13.4% of the patients. The crude 7-year LR rate was 2% (mastectomy subgroup), 31% (BCS subgroup), and 13% (BCS + RT subgroup) (P < 0.0001). RT reduced the LR rate by 65% in all histological subgroups, especially in comedocarcinoma and mixed cribriform/papillary subgroups.

The most numerous single institution series was published by the William Beaumont Hospital (USA) in 2005 [7]. Between 1981 and 1999, 410 cases were treated; 367 were managed with BCS (54 with lumpectomy alone and 313 with adjuvant RT—median dose: 45 Gy). Of these 313 patients, 298 received also a boost with a median dose of 16 Gy. Thirty patients (8.2%) experienced an ipsilateral breast tumor recurrence after breast conservative treatment; 25/313 patients (8%) after RT, 5/54 (9.3%) after BCS alone, and 2/43 (4.7%) developed a chest wall recurrence after mastectomy. Ten-year rates of LR, CSS, and OS were similar after mastectomy and breast conservative treatment. Young age (<45 years), close/positive margins, no breast irradiation, and lower electron boost energies (≤9 MeV) were associated with a higher risk of LR.

Schouten van der Velden et al. [8] published the results of a multicenter dutch retrospective study on 798 women treated between 1989 and 2003, selected by the Tumor Registry of the Comprehensive Cancer Centre East Netherland. The 5-year recurrence-free survival (RFS) was 75% for BCS alone (237 patients) compared to 91% for BCS followed by RT (153 patients) and 99% for mastectomy (408 patients) (P < 0.01). Independent risk factors for LR were treatment strategy, symptomatically detected DCIS, and presence of comedo necrosis. Margin status reached statistical significance only for patients treated with BCS.

A very large retrospective experience is reported by the Van Nuys group [9]. Nine hundred and nine cases were reported, treated from 1971 to 2000; 326 of them underwent mastectomy, 237 BCS + RT, and 346 BCS alone. In the group of patients treated conservatively (583), the LR rate was 28% after BCS alone and 20% after BCS + RT (P = 0.06), with a median time to LR of 25 and 57 months, respectively (P < 0.01). It has to be noted that in the RT group there were more patients with “close” (<1 mm) margins (35% versus 19%), and the median followup was 36 months longer. After having observed the importance of several factors (grading and comedo necrosis, size, and margins), Silverstein et al. proposed the well-known Van Nuys Prognostic Index (VNPI) [10] based on a three-point score for each predictor. In 2003, they added age to their prognostic score [11], identifying three risk subgroups: ≤39 years of age (high score), 40–60 years of age (intermediate score), and ≥61 years of age (low score). To patients with a low score (from 4 to 6), conservative surgery alone was recommended, to those with an intermediate score (from 7 to 9) postsurgical RT, and to those with a high score (from 10 to 12) mastectomy, since the LR incidence at 5 years appeared too high (around 50%) with a BCS + RT treatment.

Although a simple, and apparently easy task, this score, based on retrospective analysis of Van Nuys case studies, has not been easily reproduced in clinical practice and has not been still validated in a prospective study [12, 13].

Another collaborative group in Italy published the data of 139 cases of DCIS treated with BCS + RT, with a median followup of 81 months [14]. Actuarial OS, CSS, and RFS at 10 years were 93%, 100%, and 86%. The same group reported on 112 cases of subclinical DCIS treated between 1982 and 1993 [15]. At a median followup of 66 months, 8 LRs were observed, with a 10-year actuarial CSS and RFS of 100% and 91%, respectively.

In a recent retrospective study of the same group, in which 586 patients treated with BCS + RT were analyzed, the risk of LR was found to be 9.6% at 10 years. The risk of LR with respect to a number of known prognostic parameters (age, tumour size, nuclear grade) was evaluated. Only age resulted to be a statistically significant prognostic factor in the univariate analysis (P = 0.0009). The actuarial 10-year OS and CSS were 98.5% and 99%, respectively (data submitted for publication).

2.1. Meta-Analysis of Retrospective Studies

In 1999, Boyages et al. [2] published a meta-analysis of the most important retrospective studies for DCIS, that had undergone different treatments: mastectomy (1574 cases), BCS alone (1148 cases), and BCS + RT (1452 cases). The meta-analysis revealed that the relapse incidence was of 22.5% after BCS alone (with 43% invasive LR), 8.9% after BCS + RT (with 50% invasive LR), and of 1.4% after mastectomy (with 76% invasive LR). Considering only the conservative treatment, the RT reduced the relative LR risk of at least 50%. The major advantage on local control was noted in cases of DCIS with necrosis, comedocarcinoma, high nuclear grade, and positive or “close” margins.


3. Randomized Clinical Trials

The impact of RT after conservative surgery in women with newly diagnosed DCIS has been analyzed in four prospective randomized clinical studies. The patients had undergone conservative surgery consistent of quadrantectomy, tumorectomy, or segmental mastectomy.

In three of these studies, a comparison was made between the results of BCS alone and BCS followed by breast irradiation (two arms of randomization). A 2 × 2 factorial design was used in the fourth study; the aim was to see the effectiveness of either adjuvant RT or hormonal therapy with Tamoxifen (TAM); allocation of patients could have happened for both treatments (RT and TAM) or just for one of the two, reserving the second as the only other choice.

The first study, the American NSABP-B-17 trial [16], randomized 818 cases of DCIS, between October 1985 and December 1990, 80.4% of which mammographically diagnosed (Table 1).

The protocol required histological negative margins; however, inking of excision margins and specimen radiography were not routinely used in that era. Thus, in a central pathology review on histopathologic specimen, uncertain or positive margins were found in 17% of the cases [17].

The cumulative incidence of ipsilateral events, with a median followup of 12 years, was of 31.7% for the control group, compared to 15.7% for the group with RT (P < 0.000005); 76% were true LR within the same quadrant. Considering the invasive LR, the incidence lowered from 16.8% (control group) to 7.7% (RT group) (P = 0.00001); while for DCIS LR, it lowered from 14.6% to 8.0% (P = 0.001). Neither the cumulative incidence of contralateral tumors nor the OS (P = 0.80) differed significantly between the two groups.

Recently, the long-term results of the NSABP B-17 and B-24 trials have been published [18]. In the NSABP B-17 study, with a median followup of 207 months, the significant contribution of RT in reducing the ipsilateral events is confirmed (Table 2).

The regional recurrence and the distant metastasis incidence are comparable in the two groups; also the contralateral tumor incidence results are very similar as well as mortality from breast carcinoma or other causes.

The evaluation of the predictive factors was referred to in a publication from 1999 [17], in which were analyzed the results of a centralized pathological revision of 623 trial cases (77% of all study cases). With a median followup of 8.5 years, in the multivariate analysis only comedo necrosis was found to be an independent predictive variable for LR. However, it was observed that within all prognostic subgroups, an overall benefit from the use of RT was maintained.

In the second study, the European EORTC-10853 [19], 1010 patients, treated between March 1986 and July 1996, were randomized; in 71% of the cases the initial diagnosis was exclusively mammographic (Table 1).

The arm with RT received a total dose of 50 Gy in 25 fractions; only 5% of the patients received an additional boost with a median dose of 10 Gy. Negative margins represented one of the inclusion criteria; however, a centralized pathologic revision of 863 of the 1010 randomized cases (85%) revealed that the margins were positive or “close” (≤1 mm) for 8.5% of the cases, and not known in 13.5% cases [20].

The LR rate, with a median followup of 10.5 years, was of 26% in the control arm, compared to 15% in the RT arm (P < 0.0001). In the RT group was noted a decrease in the risk of invasive LR and DCIS LR of 42% (P = 0.0065) and of 48% (P = 0.0011), respectively (Table 2). The incidence of contralateral breast tumors, of regional and distant relapse, and OS demonstrated no significant difference within the two groups.

In the multivariate analysis of the prognostic factors, young age (≤40 years), symptomatically detected DCIS, high nuclear grade (G2-3), solid/comedo or cribriform growth pattern, and the absence of free margins were associated with an increased risk of LR. Similarly to the findings of the NSABP B-17 trial, RT reduced the risk of LR in all prognostic subgroups considered.

The third study, the Swedish SweDCIS [21], was conducted between September 1987 and December 1999; 1046 patients out of 1067 randomized women were eligible to the statistical evaluation, with a mean followup of 8.4 years. In 823/1046 cases (78.7%), the DCIS was discovered in a mammographic screening (Table 1).

In the RT arm, treatment could be given either continuously (total dose: 50 Gy, 25 fractions) or in a split-course schedule (54 Gy given in two series with a gap of two weeks), which was administered in less than 50 cases; no RT boost was given to the tumor bed. The protocol did not require pathologically negative margins, thus in 11% of the cases, the margins were positive and in 9% they were unknown. The difference of the LR rate was significant: 27.1% in the control group compared to 12.1% in the other one. The invasive LR were reduced from 12.3% to 7.2% and the DCIS LR from 14.8% to 4.9% with RT (Table 2). The incidence of contralateral events, metastasis, and death due to breast carcinoma did not present significant differences within the two groups.

Considering the main prognostic factors, a correlation between RT effectiveness and age was noted (P = 0.07), more evident for women over 60 years (risk reduction of 18%) [20].

In a previous study [22] that had investigated the histopathologic risk factors for LR by a slide revision of 2 cohort cases from the trial, high nuclear grade and necrosis were associated to a major local relapse risk. RT has conferred a reduction of relapse risk in all prognostic subgroups.

The fourth study, the English, Australian and New Zealand UK/ANZ DCIS trial [23], was conducted from May 1990 in Great Britain and September 1991 in Australia and New Zealand to August 1998 (Table 1). The protocol required the complete excision of the lesion, the radiography of the surgical specimen, and the presence of free microscopic margins. In the two arms with RT (RT, RT + TAM), the total dose was of 50 Gy in 25 fractions, without boost on the tumor bed; in the two hormonal-therapy arms (TAM, TAM + RT), the TAM dose was of 20 mg/die for 5 years.

The recent update of the study [24] has a median followup of 12.7 years, and it contains 1694 patients, 1030 of which were assigned to randomization for RT. In such a group, the incidence of ipsilateral events was of 19.4% in the control arm and of 7.1% in the RT arm (P < 0.0001), with, respectively, 9.1% and 3.3% of invasive carcinomas and 9.7% and 3.8% of noninvasive ones; the incidence of contralateral tumors was of 4.1% in the control arm and of 3.3% in the RT arm (P = 0.6) (Table 2). Overall, there was no significant difference in the death rate within the different subgroups.

It was noted an increase in cardiovascular deaths within the patients treated with RT, with or without TAM (P = 0.008), although the numbers were small. Death due to breast carcinoma proved to be higher within the patients that received hormonal treatment, but the difference was not significant [24].

3.1. The Meta-Analyses of Randomized Trials

The first meta-analysis of the four randomized trials was published by Viani et al. in 2007 [25].

The overall statistical evaluation of 3665 patients pointed out a reduction in LR risk (either invasive or DCIS) of approximately 60% with the addition of adjuvant RT, compared to excision alone. Such reduction in risk was more evident in the cases with high nuclear grade and positive margins, even though it was not possible to identify a subgroup of women with low LR risk who did not need to be treated with RT. Within the two groups, no differences appeared between the incidence of distant metastasis and the OS rate. The probability of contralateral breast carcinoma proved to be 1.53 times higher in the RT arm (3.85% versus 2.5%, P = 0.03). In the subsequent meta-analyses, which have examined the data of the four trials after a longer follow-up period, such difference was minimal and did not prove to be statistically significant.

In 2009, Goodwin et al. [26] published a systematic review and a meta-analysis of the four trials; a more detailed version was published in the Cochrane Library [27].

From the statistical analysis, conducted on 3925 women, a significant reduction of ipsilateral events with adjuvant RT resulted (HR = 0.49; 95% CI 0.41–0.58, P < 0.00001). The authors investigated the role of breast irradiation in relation to some prognostic parameters: margin status, age (>50 versus <50 years), and presence of comedo necrosis; in all the analyzed prognostic subgroups the contribution of RT was significant.

In very few cases, severe cardiovascular toxicity or the appearance of a second primary tumor was observed, but with very similar numbers within the two groups. The median followup of the trials included in the meta-analysis varied from 4.4 to 10.5 years; the authors hypothesized that with a longer followup, an increase of RT late toxicity could appear [26].

In 2010, the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) was published [28]. The statistical analysis showed that RT is able to reduce the absolute risk of ipsilateral events of 15.2% at 10 years (12.9% versus 28.1%, logrank 2P < 0.00001) and that its effectiveness does not differ significantly in relation to age, extension of the surgical procedure, association with TAM, diagnostic method, status of the margins, focality, nuclear grade, presence of comedo necrosis, architectonic pattern, and dimension of the tumor. Regarding age, a reduction of the ipsilateral events was noted in women ≥50 years of age.

The authors examined a subgroup of 291 cases out of the meta-analysis with low risk (tumor dimension ≤20 mm, negative margins and grade 1); even in such a very favourable subgroup they confirmed a significant reduction in the 10-year risk of ipsilateral events of 18.0% with RT (logrank 2P = 0.002).


4. Prognostic Factors

Actually, there is no evidence from observational studies and clinical trials that BCS plus RT is more or less effective than BCS without RT in the presence or absence of particular adverse prognostic factors, with RT being more effective in all subsets of patients.

BCS alone, even though not detrimental in terms of survival, is a treatment at high risk of LR.

Eastern Cooperative Oncology Group (ECOG) reported a registration study (ECOG E5194) aimed to prospectively identify favorable patients with DCIS treatable with local excision alone [29]. With a median followup of 6.2 years, the 7-year rate of LR was 10.5% for the 565 patients with low- or intermediate-grade DCIS; with a median followup of 6.7 years, the 7-year rate of LR was 18.0% for the 105 patients with high-grade DCIS. On multivariate analysis, no variable was significantly associated with LR.

Another study has demonstrated similar findings for a cohort of patients treated with BCS alone [30].

Wong et al. [36] reported on 158 patients treated with wide excision alone, with a minimum negative margin width of 1.0 cm. The 5-year rate of LR was 12%; the study, therefore, was closed early because of the negative results.

4.1. Clinical Factors

The major clinical factors associated with an increased risk of LR following breast-conserving treatment for DCIS are symptomatic presentation and young patient age at diagnosis [37].

4.2. Pathologic Factors

The most frequently reported factors associated with a higher risk of LR are high nuclear grade, comedo necrosis, and larger tumor size.

In the NSABP-B17 trial, the presence of comedo necrosis was associated with a higher risk of LR, limited, however, to the group of patients treated with excision alone [18]. In that group, LR rate at 8 years was 40% for cases with moderate or marked comedo necrosis compared to 23% for patients without it.

Data published by Silverstein et al. [10] showed that margin widths of 10 mm or more have a risk of LR unaffected by nuclear grade and addition of RT. In contrast, these factors remained significant in the group of patients with small margin widths [38].

The impact of DCIS grade on LR risk appears to be related to the length of followup, as emphasized in the study of Solin et al. [5]. In this study, comedo architecture and nuclear grade 3 had a significantly higher 5-year LR rate; the difference, however, was no longer statistically significant at 10 years.

These data suggest that risk factors for noninvasive and invasive LR may not be identical, that the analysis of the combination of these events into a single group may obscure important differences and that the biological basis for noninvasive and invasive LR may be different.

4.3. Margins

Multiple retrospective studies and some clinical prospective trials have shown that achieving pathologically confirmed negative margins is associated with a decreased rate of LR. The evaluation of the involvement of the margins of excision is one of the few clinical variables that can be controlled even though the definition of a negative margin varies from study to study (1, 2, 5, or even 10 mm).

Dunne et al. [39] reported a meta-analysis of 4660 patients treated with BCS + RT from 22 studies with data on margins of resection. The odds ratio for LR was 2.56 (P < 0.05), 2.89 (P < 0.05), and 1.51 (P > 0.05) for a minimum negative margin width of no tumor cells, 1 mm and 2 mm on ink, respectively.

A minimum negative margin width of 2 mm was considered appropriate in the setting of adding RT after lumpectomy. On the contrary, a minimum negative margin width of 10 mm has been recommended when using lumpectomy alone [38].

In some series, a small number of patients with close or positive margins is reported. In these cases with focally close or positive margin of resection, reexcision is the preferred next step. If a reexcision cannot be performed, definitive irradiation can be delivered with a slightly higher risk of local failure. The excess risk of LR in this setting is estimated of approximately 5%–7% [39, 40].


5. Salvage Treatment for Local Recurrence

Since DCIS is associated with a low rate of mortality, analyses of the success of treatment should focus on recurrence.

One of the arguments advanced in favor of omitting radiation after BCS at the time of initial presentation is the hypothetical ability to repeat a salvage breast conservative treatment. However, few data have been reported on this argument. Salvage mastectomy is frequently indicated following LR, particularly when reexcision would be cosmetically unacceptable, or when an adjuvant RT was previously performed.

The rate of salvage breast conservation is only 42%–52% after primary BCS and some patients can reject secondary breast conservation in favor of mastectomy. Thus, preventing LR by adding RT at the time of initial treatment may be a more important long-term strategy.

A dedicated study [41] reported 90 patients with local or local-regional recurrence as the site of first failure. Salvage surgery was mastectomy for 76/90 (84%) patients. The median followup was 5.5 years after salvage treatment; 10-year OS and CSS were 83% and 95%, respectively; 10-year rate of freedom from distant metastases was 91%.

Local and local-regional recurrences can be salvaged with high rates of survival and freedom from distant metastases. Careful followup is warranted for the early detection of potentially salvageable recurrences.


6. Particular Aspects of DCIS Irradiation
6.1. Role of the Boost

The advantage of an additional boost to the tumor bed after BCS and whole breast irradiation (WBI) for invasive breast cancer has been confirmed by controlled clinical trials [42, 43] and is now a standard of care. Whether this is applicable to patients with pure ductal carcinoma in situ (DCIS) is unclear.

The importance of a boost in the local control of DCIS has been examined in 6 retrospective studies [3135, 44] (Table 3), while no prospective randomized study has been published so far on this issue.

In two trials, the role of the addition of a boost is studied: the BIG 3-07/TROG 07.01 and the BONBIS multicenter study [45, 46]. In both trials the accrual of the patients is still ongoing.

Of particular interest are the results of the international multicenter retrospective study by Omlin et al. [31]: 373 patients ≤45 years old were treated with BCS only (15%), BCS followed by WBI (45%), or BCS and WBI followed by a boost on the tumor bed (40%). The authors observed a progressive increase of local relapse-free survival at 10 years, starting from BCS without WBI (46%), to WBI without boost (72%), to WBI followed by boost (86%) (P < 0.0001).

In the multivariate analysis, margin state and RT dose resulted as independent predictive factors of local relapse-free survival; the major advantage correlated to the delivery of the boost was noticed in young women (≤39 years).

Considering the limits of this study (retrospective design, with a very long accrual period of 26 years and lacking a centralized revision of tumor-sample histology), and while waiting for the results of the randomized clinical trials in course, it would be appropriate to consider a boost after WBI for women aged 45–50 or younger.

6.2. Hypofractionated RT

Recently, a considerable interest for hypofractionated RT schedules was noted, either in the form of whole- or partial-breast treatment.

The considerable duration of the whole treatment with conventional RT (from 5 to 6.5 weeks), associated with the distance from the patients home to the Radiotherapy Centers and the long waiting lists, represents matter-of-fact criticality factors of standard breast RT.

6.2.1. Hypofractionated WBI

The efficacy of hypofractionated WBI, in the treatment of invasive breast cancer after conservative surgery, has been confirmed by retrospective studies and by some recent randomized trials, which account excellent results both in terms of local-regional control and cosmetic outcome [47].

As long as DCIS is concerned, so far only two prospective phase I and II studies have been published [48, 49].

The study of Constantine et al. [49] is the only one that included exclusively patients with mammographically detected pure DCIS (59 cases) treated with hypofractionated WBI, for a total dose of 42 Gy in 15 fractions. With a still limited followup (36 months) no LRs or contralateral tumors were found.

The study of Freedman et al. [48] examined together women with early invasive carcinoma and with DCIS. The patients underwent a treatment of the whole breast with IMRT, at a total dose of 45 Gy in 20 fractions and a concomitant boost on the tumor bed to a total dose of 56 Gy (2.8 Gy/fr. in 20 fractions). To-date, only data relative to acute toxicity and cosmetic results have been published.

Also some retrospective studies [35, 44, 50, 51] show optimal results in terms of local control in DCIS with hypofractionated treatment.

No phase III prospective study has been published until now; in 2007, the above-mentioned international multicenter BIG 3-07/TROG 07.01 trial was initiated, and it confronted both the conventional RT schedule versus the hypofractionated one, and the boost versus no-boost delivery [45, 46]. The patients' accrual has not been closed so far: some years are needed before the results can be published.

6.2.2. Partial Breast Irradiation (PBI)

PBI has been widely proposed as the treatment for early-stage invasive breast cancer; options include brachytherapy techniques (using either the interstitial catheters or the intracavitary device MammoSite), external-beam RT (3D-CRT or IMRT), and intraoperative radiotherapy.

It seems more controversial when it is used to treat DCIS, based on the knowledge of the growth pattern of this tumor within the complex ductal-lobular system of the breast [52].

According to a recent Consensus Statement of the ASTRO (American Society for Radiation Oncology) [53], which has established the criteria for the inclusion of PBI, outside the clinical trials, the partial irradiation for pure DCIS is to be evaluated with caution if the tumor diameter is ≤3 cm and is not indicated if the diameter is >3 cm. Therefore, few studies have documented the efficacy of PBI in treating DCIS so far [54].

The American Society of Breast Surgeons (ASBS) has recently published an update on the DCIS case studies included in the MammoSite Registry Trial, that represents the widest prospective database published until now [55]. For 194 patients, with a median followup of 54.4 months, the 5-year actuarial LR rate is of 3.39% and the cosmetic results are favorable in 92% of the cases.

In 2005, a phase III prospective, randomized, multicenter study, NSABP B-39/RTOG 0413, was started [45, 54]. It compared WBI to PBI. Patients with DCIS or with stage I or II invasive carcinoma (T ≤ 3 cm), N− or N+ (≤3 N+), are being treated with lumpectomy and then randomized to either WBI (±boost) or PBI with one of the 3 following techniques: interstitial multicatheter brachytherapy (34 Gy–3.4 Gy/fr, BID), brachytherapy with MammoSite (34 Gy–3.4 Gy/fr, BID), 3D-CRT (38.5 Gy–3.85 Gy/fr, BID).

The results of this trial will be very important in finding out the long-term efficacy of PBI, both for invasive carcinoma and DCIS.

It should be noted that PBI does not represent a therapeutic standard, neither for invasive carcinoma, nor for DCIS; the randomized studies in progress will have to evaluate the relapse risk, the cosmetic results, and long-term toxicity.


7. Conclusions

Randomized trials provide consistent evidence that DCIS treated with breast-conserving surgery plus radiation compared to BCS alone results in a reduction of noninvasive LR and of invasive LR by approximately 50%. As breast cancer specific survival after DCIS is uniformly excellent, the major measure of treatment effectiveness has generally been the LR rate.

Subset analyses of randomized controlled trials do not point out to differential effectiveness of surgery versus RT in the presence of some adverse prognostic factors. This suggests that treatment alone may not eliminate the adverse prognosis. However, it also suggests that for patients with adverse prognostic features, treatment may be particularly important.

Studies of new irradiation modalities (PBI, hypofractionation) in DCIS patients are currently ongoing and deserve further attention.


References
1. Leonard GD,Swain SM. Ductal carcinoma in situ, complexities and challengesJournal of the National Cancer InstituteYear: 2004961290692015199110
2. Boyages J,Delaney G,Taylor R. Predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysisCancerYear: 199985361662810091735
3. Joslyn SA. Ductal carcinoma in situ: trends in geographic, temporal, and demographic patterns of care and survivalBreast JournalYear: 2006121202716409583
4. Smith GL,Smith BD,Haffty BG. Rationalization and regionalization of treatment for ductal carcinoma in situ of the breastInternational Journal of Radiation Oncology Biology PhysicsYear: 200665513971403
5. Solin LJ,Fourquet A,Vicini FA,et al. Long-term outcome after breast-conservation treatment with radiation for mammographically detected ductal carcinoma in situ of the breastCancerYear: 200510361137114615674853
6. Cutuli B,Fay R,Cohen-Solal-Le Nir C,et al. Ductal carcinoma in situ of the breast: analysis of 882 casesPresse MedicaleYear: 20043328389
7. Vargas C,Kestin L,Go N,et al. Factors associated with local recurrence and cause-specific survival in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy or mastectomyInternational Journal of Radiation Oncology Biology PhysicsYear: 200563515141521
8. Schouten van der Velden AP,van Vugt R,Van Dijck JAAM,Leer JWH,Wobbes T. Local recurrences after different treatment strategies for ductal carcinoma in situ of the breast: a population-based study in the East NetherlandsInternational Journal of Radiation Oncology Biology PhysicsYear: 2007693703710
9. Silverstein MJ. The Van Nuys/University of Southern California experience by treatmentDuctal Carcinoma in Situ of the BreastYear: 20022nd editionPhiladelphia, Pa, USALippincot Williams and Wilkins337342
10. Silverstein MJ,Lagios MD,Craig PH,et al. A prognostic index for ductal carcinoma in situ of the breastCancerYear: 19967711226722748635094
11. Silverstein MJ. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breastAmerican Journal of SurgeryYear: 2003186433734314553846
12. De Mascarel I,Bonichon F,Macgrogan G,et al. Application of the Van Nuys prognostic index in a retrospective series of 367 ductal carcinomas in situ of the breast examinated by serial macroscopic sectioning: Practical considerationsBreast Cancer Research and TreatmentYear: 200061215115910942101
13. MacAusland SG,Hepel JT,Chong FK,et al. An attempt to independently verify the utility of the Van Nuys Prognostic Index for ductal carcinoma in situCancerYear: 2007110122648265317960606
14. Amichetti M,Caffo O,Richetti A,et al. Ten-year results of treatment of ductal carcinoma in situ (DCIS) of the breast with conservative surgery and radiotherapyEuropean Journal of CancerYear: 19973310155915659389915
15. Amichetti M,Caffo O,Richetti A,et al. Subclinical ductal carcinoma in situ of the breast: treatment with conservative surgery and radiotherapyTumoriYear: 199985648849310774571
16. Fisher B,Land S,Mamounas E,Dignam J,Fisher ER,Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experienceSeminars in OncologyYear: 200128440041811498833
17. Fisher ER,Dignam J,Tan-Chiu E,et al. Pathologic Findings from the National Surgical Adjuvant Breast Project (NSABP) Eight-Year Update of Protocol B-17CancerYear: 199986342943810430251
18. Wapnir IL,Dignam JJ,Fisher B,et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCISJournal of the National Cancer InstituteYear: 2011103647848821398619
19. Bijker N,Meijnen P,Peterse JL,et al. 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 groupJournal of Clinical OncologyYear: 200624213381338716801628
20. Bijker N,Peterse JL,Julien JP,et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853Journal of Clinical OncologyYear: 20011982263227111304780
21. Holmberg L,Garmo H,Granstrand B,et al. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breastJournal of Clinical OncologyYear: 20082681247125218250350
22. Ringberg A,Nordgren H,Thorstensson S,et al. Histopathological risk factors for ipsilateral breast events after breast conserving treatment for ductal carcinoma in situ of the breast—results from the Swedish randomised trialEuropean Journal of CancerYear: 200743229129817118648
23. Coordinating Committee on Cancer Research Ductal Carcinoma in situ Working Party on behalf of DCIS trialists in the UK UK,Australia,New Zealand. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trialLancetYear: 20033629510212867108
24. Cuzick J,Sestak I,Pinder SE,et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trialThe Lancet OncologyYear: 2011121212921145284
25. Viani GA,Stefano EJ,Afonso SL,et al. Breast-conserving surgery with or without radiotherapy in women with ductal carcinoma in situ: a meta-analysis of randomized trialsRadiation OncologyYear: 200721, article no. 28
26. Goodwin A,Parker S,Ghersi D,Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breast—a systematic review of the randomised trialsBreastYear: 200918314314919447038
27. Goodwin A,Parker S,Ghersi D,Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breastCochrane Database of Systematic ReviewsYear: 20091 Article ID CD000563..
28. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breastJournal of the National Cancer Institute. MonographsYear: 201020104116217720956824
29. Hughes LL,Wang M,Page DL,et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology GroupJournal of Clinical OncologyYear: 200927325319532419826126
30. Balleine RL,Webster LR,Davis S,et al. Molecular grading of ductal carcinoma in situ of the breastClinical Cancer ResearchYear: 200814248244825219088042
31. Omlin A,Amichetti M,Azria D,et al. Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer NetworkLancet OncologyYear: 20067865265616887482
32. Yerushalmi R,Sulkes A,Mishaeli M,et al. Radiation treatment for ductal carcinoma in situ (DCIS): is a boost to the tumor bed necessary?NeoplasmaYear: 200653650751017167720
33. Julian TB,Land SR,Wang Y,et al. Is boost therapy necessary in the treatment of DCIS?Journal of Clinical OncologyYear: 200826, abstract 537
34. Monteau A,Sigal-Zafrani B,Kirova YM,et al. Ductal carcinoma in situ of the breast with close or focally involved margins following breast-conserving surgery: treatment with reexcision or radiotherapy with increased dosageInternational Journal of Radiation Oncology Biology PhysicsYear: 200975410211028
35. Wai ES,Lesperance ML,Alexander CS,et al. Effect of radiotherapy boost and hypofractionation on outcomes in ductal carcinoma in situCancerYear: 20111171546220803608
36. Wong JS,Kaelin CM,Troyan SL,et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breastJournal of Clinical OncologyYear: 20062471031103616461781
37. Meijnen P,Oldenburg HSA,Peterse JL,Bartelink H,Rutgers EJT. Clinical outcome after selective treatment of patients diagnosed with ductal carcinoma in situ of the breastAnnals of Surgical OncologyYear: 200815123524317987342
38. Silverstein MJ,Lagios MD,Groshen S,et al. The influence of margin width on local control of ductal carcinoma in situ of the breastNew England Journal of MedicineYear: 1999340191455146110320383
39. Dunne C,Burke JP,Morrow M,Kell MR. Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situJournal of Clinical OncologyYear: 200927101615162019255332
40. Solin LJ,Fourquet A,Vicini FA,et al. Long-term outcome after breast-conservation treatment with radiation for mammographically detected ductal carcinoma in situ of the breastCancerYear: 200510361137114615674853
41. Solin LJ,Fourquet A,Vicini FA,et al. Salvage treatment for local or local-regional recurrence after initial breast conservation treatment with radiation for ductal carcinoma in situEuropean Journal of CancerYear: 200541121715172316043350
42. Romestaing P,Lehingue Y,Carrie C,et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, FranceJournal of Clinical OncologyYear: 19971539639689060534
43. Bartelink H,Horiot JC,Poortmans PM,et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-Year results of the randomized boost versus no boost EORTC 22881-10882 trialJournal of Clinical OncologyYear: 200725223259326517577015
44. Wong P,Lambert C,Agnihotram RV,David M,Duclos M,Freeman CR. Ductal carcinoma in situ-the influence of the radiotherapy boost on local controlInternational Journal of Radiation Oncology, Biology, PhysicsYear: 2012822e153e158
45. Polgár C,Kahán Z,Orosz Z,et al. The role of radiotherapy in the conservative treatment of ductal carcinoma in situ of the breastPathology and Oncology ResearchYear: 200814217919218438723
46. Azria D,Auvray H,Barillot I,et al. Radiothérapie des carcinomes canalaires in situ: impact du complément d’irradiation du lit tumoralCancer/RadiothérapieYear: 2008126-7571576
47. Whelan TJ,Kim DH,Sussman J. Clinical experience using hypofractionated radiation schedules in breast cancerSeminars in Radiation OncologyYear: 200818425726418725113
48. Freedman GM,Anderson PR,Goldstein LJ,et al. Four-week course of radiation for breast cancer using hypofractionated intensity modulated radiation therapy with an incorporated boostInternational Journal of Radiation Oncology Biology PhysicsYear: 2007682347353
49. Constantine C,Parhar P,Lymberis S,et al. Feasibility of accelerated whole-breast radiation in the treatment of patients with ductal carcinoma in situ of the breastClinical Breast CancerYear: 20088326927418650158
50. Livi L,Stefanacci M,Scoccianti S,et al. Adjuvant hypofractionated radiation therapy for breast cancer after conserving surgeryClinical Oncology (Royal College of Radiologists)Year: 2007192120124
51. Williamson D,Dinniwell R,Fung S,Pintilie M,Done SJ,Fyles AW. Local control with conventional and hypofractionated adjuvant radiotherapy after breast-conserving surgery for ductal carcinoma in-situRadiotherapy and OncologyYear: 201095331732020400190
52. Silverstein MJ. Ductal Carcinoma in Situ of the BreastYear: 20022nd editionPhiladelphia, Pa, USALippincot Williams and Wilkins
53. Smith BD,Arthur DW,Buchholz TA,et al. Accelerated partial breast irradiation Consensus Statement from the American Society for Radiation Oncology (ASTRO)International Journal of Radiation Oncology Biology PhysicsYear: 20097449871001
54. Park SS,Grills IS,Chen PY,et al. Accelerated partial breast irradiation for pure ductal carcinoma in situInternational Journal of Radiation Oncology, Biology, and PhysicsYear: 2011812403408
55. Jeruss JS,Kuerer HM,Beitsch PD,Vicini FA,Keisch M. Update on DCIS outcomes from the american society of breast surgeons accelerated partial breast irradiation registry trialAnnals of Surgical OncologyYear: 2011181657120577822

Article Categories:
  • Review Article


Previous Document:  No excess mortality in patients aged 50 years and older who received treatment for ductal carcinoma ...
Next Document:  Horizontal violence and the quality and safety of patient care: a conceptual model.