Originally published as JCO Early Release 10.1200/JCO.2005.02.9975 on February 6 2006

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Prospective Study of Wide Excision Alone for Ductal Carcinoma in Situ of the Breast

From the Departments of Radiation Oncology, Surgery, Pathology, and Biostatistics and Computational Biology, Dana-Farber/Brigham and Women's Cancer Center; Departments of Surgery and Pathology, Massachusetts General Hospital; and Departments of Surgery and Pathology, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, MA

Address reprint requests to Julia Wong, MD, Department of Radiation Oncology, Dana-Farber Cancer Institute, 44 Binney St, L2, Boston, MA 02115; e-mail: jwong{at}lroc.harvard.edu

	ABSTRACT

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PURPOSE: It has been hypothesized that wide excision alone with margins 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial.

METHODS: Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of 2.5 cm treated with wide excision with final margins of 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients.

RESULTS: In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease.

CONCLUSION: Despite margins of 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.

	INTRODUCTION

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Ductal carcinoma in situ (DCIS) of the breast is a noninvasive or preinvasive lesion characterized by malignant ductal cells confined to the duct lumen, without evidence of invasion into the adjacent breast stroma. With improvements in mammographic screening and pathologic evaluation resulting in the detection of progressively smaller areas of DCIS, the use of breast-conserving approaches for DCIS has increased, in parallel with the widespread acceptance of breast-conserving surgery and radiation therapy as a standard treatment option for early-stage, invasive breast cancer.

Data from three randomized controlled trials have shown that radiation therapy reduces local recurrence after breast-conserving surgery for DCIS by approximately 50% to 60%.^1-3 Within these randomized trials, no subsets have been identified that do not benefit from radiation therapy. However, radiation therapy has not provided a clear survival advantage, is time consuming, and has some toxicity. Consequently, there has been interest in identifying patients with small DCIS lesions with favorable features who might be treated effectively with local excision alone. Retrospective analyses suggest that patients with small, low-grade DCIS or DCIS with margins of at least 1 cm have low local treatment failure rates with excision alone, without radiation therapy.^4,5

Our aim was to evaluate in a prospective study whether localized low- or intermediate-grade DCIS, diagnosed with modern mammography and subjected to careful pathologic evaluation, could be treated with wide excision alone and result in acceptably low local recurrence rates.

	METHODS

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Eligibility and Enrollment
Patients seen at one of the hospitals comprising the Dana-Farber/Harvard Cancer Center (Brigham and Women's Hospital, Massachusetts General Hospital, Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Boston, MA) either for initial mammography and surgery or for consultation after initial mammography and surgery who were diagnosed with DCIS (without invasion) were eligible potentially. Patients signed informed consent for this study, which was approved by the respective institutional review boards.

To be eligible, patients were required to undergo high-quality mammograms with magnification views of the area containing calcifications suggestive of disease (ideally, before excision). The mammographic size of the lesion was determined by the (demagnified) extent of calcifications or by palpation, and the clinical extent of DCIS was required to be 2.5 cm. Patients with grade 1 or 2 DCIS, defined by the predominant nuclear grade, were eligible. The presence of a small number of DCIS cells with grade 3 nuclei was not a reason for exclusion. The presence of necrosis was recorded but necrosis was not taken into consideration in the grading of these lesions, which was based entirely on nuclear grade. At least some of each patient's histologic slides were reviewed by a dedicated breast pathologist at one of the three main institutions to confirm eligibility. An initial biopsy or re-excision specimen from an outside institution had to be processed in accordance with the requirements of the protocol pathologists to be acceptable.

Patients were required to undergo wide excision with or without re-excision. Complete resection of the area of DCIS with a histologic margin of at least 1 cm (or a totally negative re-excision) was required. Margins were inked. A re-excision was performed if initial margins were less than 1 cm or not assessable. If the DCIS was located within 1 cm of the skin or chest wall fascia, and the surgeon noted this and oriented the specimen in such a way that the pathologist could assess the margins in relation to these limiting structures, the patient was considered eligible if the final margins were uninvolved but less than 1 cm. A specimen radiograph was required. If the specimen radiograph did not verify that all calcifications suggestive of disease were removed, a negative postoperative mammogram was required. Patients who did not have magnification views before excision were required to have postexcision mammograms with magnification views. The cumulative volume of breast tissue excised was defined as the total tissue volume. This was calculated by multiplying the three dimensions of each excision specimen. If a patient had more than one specimen per surgical procedure or more than one excision, the volumes of the multiple specimens were summed.

Protocol entry was required to be within 3 months of the last surgical procedure. Retrospective patient entry was not permitted.

Exclusion criteria included nipple discharge at presentation; a history of nonbreast malignancies (other than squamous or basal cell carcinoma of the skin, or carcinoma in situ of the cervix); a previous breast cancer (ipsilateral or contralateral, invasive or DCIS) and simultaneous bilateral DCIS. Chemotherapy and tamoxifen were not permitted. Patients were evaluated by a surgeon and radiation oncologist to determine protocol eligibility, and agreed to follow-up examinations and mammography. Follow-up consisted of physical examination at least every 6 months by the surgeon or radiation oncologist, and mammograms of the ipsilateral breast every 6 months for 5 years, then annually. Magnification views of the biopsy cavity were recommended. Mammograms of the contralateral breast were obtained annually.

Statistical Analysis
The study originally had a sequential design using the exact conditional Poisson test with planned analyses at a maximum of three time points (100, 200, and 350 patient-years of follow-up) and a planned maximum accrual of 100 patients. Termination of accrual was required if seven local recurrences were observed before a total combined follow-up time of 100 patient-years, if eight local recurrences were observed before 200 patient-years, or if nine local recurrences were observed before 350 patient-years. Using this design, the overall probability of a type I error (ie, the probability of rejecting the original null hypothesis of a 7% 5-year local recurrence rate if it were true) was 6% and the power (ie, the probability of rejecting the null hypothesis if the recurrence rate were truly 20%) was 94%. Both invasive and DCIS recurrences were to be counted. In a sequential design such as this, the stopping rules are calculated by using up a prespecified amount of the type I error probability at each prespecified analysis time. If the true treatment failure rate is far from the null and alternative hypothesis treatment failure rates, then the stopping rules are incorrect; for this reason many statisticians would advise changing the prespecified rules if the observed treatment failure rate is far from the null and alternative hypotheses.

In May 1999, with one recurrence reported among the 99 patients entered onto the trial and a total of 199 patient-years of follow-up, the observed treatment failure rate was 0.5% per year—far from the hypotheses of 1.4% to 4% per year. At that time, the maximum accrual was increased to 200 to facilitate future subgroup analysis. The goal was changed to allow us to distinguish between a 1% and a 2% annual ipsilateral recurrence rate (ie, a 5% and a 10% 5-year recurrence rate). New stopping rules were set up to terminate accrual if eight ipsilateral recurrences were observed before a total combined follow-up of 200 patient years, 13 recurrences were observed before 700 patient-years, or 19 recurrences were observed before 1,200 patient-years. The change in the stopping rules and maximum accrual was calculated in such a way as to preserve the overall type I error probability, while taking into account the results of one interim analysis that had already been done. Using the amended design, the overall type I error probability was 5% and the power was 88%.

We recruited patients from May 1995 to July 2002. The study was closed to additional enrollment at that time because the stopping boundary was crossed. The sequential design requires that the primary analysis be done on data existing at the time of study closure, given that this is the only analysis that has the power and overall type I error that was used in planning the stopping rules.

	RESULTS

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In July 2002, with 158 patients enrolled, the stopping boundary was reached and the study was closed to accrual. At that time, there were 13 ipsilateral recurrences with a total of 477 reported patient-years of follow-up, meaning that there would be at least 13 recurrences by the time of the scheduled review at 700 patient-years of follow-up. The following analysis represents data obtained when all patients had been observed up to or just beyond July 2002, and includes a total of 541 patient-years of follow-up.

Patient characteristics are listed in Table 1. Five patients were deemed ineligible retrospectively but were included in the analysis: one had prior DCIS; one had prior thyroid cancer; one entered 92 days after last breast surgery; one entered 101 days after last breast surgery; and one was enrolled because the initial review at the outside hospital, as well as rereview at our institution, confirmed the presence of DCIS. However, when the designated reviewer examined the slides, there was controversy regarding whether the pathology met criteria for DCIS; the study pathologists ultimately classified the cells as atypical ductal hyperplasia only.

Pathologic features are listed in Table 2. Some lesions were removed mostly or completely on core biopsy, leading to difficulties with size assessment. Pathologic size was evaluated in several ways: number of blocks containing DCIS, number of low-powered fields containing DCIS (data not shown), and largest single diameter of DCIS (data not shown). No single mode of measurement was available for all 158 patients. The most commonly used size measurement at our institution is number of blocks involved. Ninety-six percent had size measured by number of blocks containing DCIS. The median number of blocks containing DCIS was two (range, one to nine blocks).

Thirteen local recurrences occurred as the site of first treatment failure between 0.6 and 5.2 years after study entry. The rate of ipsilateral local recurrence was 2.4% per patient-year (Poisson 95% CI, 1.3% to 4.1%), corresponding to a 5-year rate of approximately 12%. Initial clinical and tumor characteristics of the 13 patients who experienced tumor recurrence are listed in Tables 1 and 2. Nine (69%) of the recurrences were DCIS and four (31%) were invasive. Twelve were detected mammographically and one was palpable (with a corresponding mammographic abnormality). Four were detected on ipsilateral mammograms obtained at 6-month intervals; eight were detected on yearly bilateral mammograms. Ten recurrences occurred in the same quadrant as the initial DCIS, and three were elsewhere in the ipsilateral breast. Of the four patients who experienced local recurrence with invasive disease, none had evidence of metastasis on axillary surgery, all were smaller than 1 cm on review, and none had associated lymphatic vessel invasion. None of the nine patients with DCIS recurrences had axillary nodes sampled. Patients who had some grade 3 nuclei in their otherwise predominantly grade 1 to 2 lesions were more likely to have a recurrence than patients without any grade 3 nuclei. Nevertheless, even if the patients with some grade 3 nuclei were omitted, the local recurrence rate in the other patients was still substantial.

The study had enough patients to have reasonable CIs for recurrence rates for three covariates, but there are more covariates of interest (in Tables 1 and 2) than the maximum number of local recurrences permitted by the sequential design. For this reason, the association of these many covariates with local recurrence was not formally analyzed, other than by providing estimated recurrence rates in Tables 1 and 2.

Other sites of first failure were as follows: eight patients developed contralateral breast cancer (five invasive, three DCIS), and three patients had another malignancy (ovarian, colon, and renal cancer). Two patients developed both ipsilateral recurrence and contralateral breast cancer; one had ipsilateral DCIS (detected incidentally at the time of prophylactic mastectomy) 8 months after contralateral DCIS, and the other had a contralateral DCIS 3.3 years after her ipsilateral DCIS recurrence. One patient died as a result of cardiac causes unrelated to her DCIS or its treatment.

Of the four patients who had ipsilateral invasive disease as the first site of treatment failure, three underwent excision plus radiation therapy (two also received hormonal therapy); the fourth patient underwent mastectomy (and received hormonal therapy). All four are free of further recurrence 13, 19, 38, and 62 months later, respectively. Of the nine patients who had ipsilateral DCIS as the first site of treatment failure, six underwent excision plus radiation therapy (three received hormonal therapy) and three underwent mastectomy without hormonal therapy. All nine are free of further recurrence 10, 13, 18, 25, 25, 29, 44, 45, and 65 months later, respectively. No patient has developed distant metastasis. Of the four patients who underwent mastectomy for local recurrence, one had an incidental finding of ipsilateral DCIS after what was considered to be a prophylactic ipsilateral mastectomy done at the time of mastectomy for a contralateral DCIS; the other three chose mastectomy over breast conservation with radiation therapy (two chose bilateral mastectomy and one chose unilateral mastectomy).

	DISCUSSION

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In this study, the omission of radiation therapy after wide excision alone for DCIS resulted in a cumulative local recurrence rate of 12% at 5 years of follow-up, despite careful initial mammographic and pathologic assessment, and limiting the study to patients with favorable features, such as small, low- or intermediate-grade lesions and margins of at least 1 cm. Previous large, randomized studies have shown that radiation therapy after excision reduces local recurrence to a greater absolute extent in patients at higher risk for recurrence⁶; however, none of these studies has identified a large subgroup that clearly does not benefit from radiation therapy. It is worth noting, however, that when radiation therapy was used, margins were often smaller than 1 cm, and no survival advantage has been demonstrated with the addition of radiation therapy.

With improvements in mammographic and pathologic evaluation, there has been increased interest in determining whether there are subgroups of patients with DCIS who have a low rate of local recurrence in the absence of radiation therapy. Silverstein et al⁴ suggested that small, low-grade lesions may have a favorable prognosis and not require radiation therapy. In addition, Silverstein et al⁵ have proposed that radiation therapy may not be necessary for DCIS excised with margins of at least 1 cm, based on their retrospective review of 469 patients treated with or without radiation therapy. They observed an 8-year local recurrence rate of only 3% among 93 patients with margins of 1 cm or greater who did not receive radiation therapy. Although these data certainly are provocative and hypothesis generating, the retrospective nature of the data, whereby the treatment was selected by the treating physician, raises the possibility of bias. This was also a highly selected group of patients: the unirradiated patients had shorter follow-up than did the irradiated patients, two different cohorts of patients were included, and some of the patients were treated as early as 1972, an era when mammographic evaluation was not comparable with the techniques employed currently. The detailed pathologic evaluation used in that study (consisting of sequential embedding), although commendable, may be cost prohibitive and not practical for use by many centers, thereby limiting generalizability. In addition, the surgical technique often included a large, en bloc excision of the skin and pectoralis fascia, which differs from the technique used in this study and that used in general practice.

The Nottingham group has reported in abstract form results of a prospective study of wide excision alone with 1-cm margins for patients with DCIS.⁷ Their study included 256 patients accrued from 1988 to 2001 with a mean follow-up time of 86 months; grade was not stated. A crude local recurrence rate of 11% (28 of 256) was reported, with 10 DCIS-only recurrences and 18 invasive recurrences. Three patients developed regional disease and one died. Twenty-four of the recurrences occurred in the 46 patients who underwent re-excision. These results are not inconsistent with the current study, showing local recurrence rates of greater than 1% per year, and indicate that a substantial number of patients experience local recurrence despite undergoing wide excision with margins of at least 1 cm.

Our prospective data suggest that a margin of 1 cm or greater, without radiation therapy, is not sufficient to provide low recurrence rates for small, low- or intermediate-grade DCIS. The recurrence rate in this ostensibly favorable population was high enough that we were compelled by the statistical and ethical bounds of the protocol to cease enrollment short of our accrual goal. This action underscored the risk of recurrence in the absence of radiation therapy or tamoxifen, but also made it impossible to analyze factors formally that may predict for recurrence in a population like this (by virtue of the small numbers).

Of note, in our study, ipsilateral mammograms were required at frequent (6-month) intervals during the first 5 years of follow-up, with magnification views suggested. Given that four local recurrences were detected on 6-month ipsilateral follow-up mammograms, rather than on the bilateral mammograms obtained yearly, it is possible that this frequent follow-up plan resulted in local recurrences being identified earlier, and that with yearly follow-up these recurrences would have manifested themselves at a later time.

We note several limitations to our study. Although this was a prospective trial, it was a single-arm trial, and small patient numbers limited our ability to perform subset analysis. We consider our central pathology review by three dedicated breast pathologists to be a strength; however, some might feel that this limits generalizability to the community at large. Our follow-up time is also relatively short, given that the study was forced to cease enrollment early and the analysis is based on the results at that time. In a small proportion of patients (number unknown), raloxifene was prescribed for bone-loss prevention during the follow-up period, and it is not clear if these patients' risk for local recurrence was lowered by this intervention.

At present, it remains unclear how to identify patients with DCIS who have a low recurrence rate with excision alone. An ongoing Radiation Therapy Oncology Group trial (RTOG 9804) is randomly assigning patients to radiation therapy or observation, with or without tamoxifen in either group. Tamoxifen use is not randomly assigned. The closed Eastern Cooperative Oncology Group trial (ECOG 5194) similarly is evaluating excision alone for DCIS (tamoxifen optional). Additional studies, perhaps using molecular techniques, might be able to better define the most favorable subgroups for wide excision without radiation therapy. Adjuvant hormonal therapy, specifically tamoxifen, is also becoming more standard in the management of estrogen receptor–positive DCIS, especially in the setting of radiation therapy.^8-10 The role of hormonal therapy after excision alone remains to be defined, but limited data thus far suggest that its effect after wide excision alone is modest at best.³

Although the majority of the local recurrences in this study were noninvasive, and all patients were treated successfully with salvage therapy (at least with short follow-up), the risk of an invasive recurrence and its possible impact on survival are issues of concern. One should also consider the psychological effects of a local recurrence, even in the absence of an effect on survival.¹¹ Patients need to be apprised of these risks, as well as the risks of radiation therapy, and make informed decisions with their physicians about the use of radiation therapy based on their individual clinical situations and perceptions of risk and benefit.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Susan L. Troyan, Rebecca Gelman, Susan C. Lester, Stuart J. Schnitt, Jay R. Harris, Barbara L. Smith, Carolyn M. Kaelin, Dennis C. Sgroi Administrative support: Barbara J. Silver Provision of study materials or patients: Julia S. Wong, Carolyn M. Kaelin, Susan L. Troyan, Michele A. Gadd, Susan C. Lester, Stuart J. Schnitt, Dennis C. Sgroi, Jay R. Harris, Barbara L. Smith Collection and assembly of data: Julia S. Wong, Carolyn M. Kaelin, Susan L. Troyan, Michele A. Gadd, Rebecca Gelman, Susan C. Lester, Stuart J. Schnitt, Dennis C. Sgroi, Barbara J. Silver, Jay R. Harris, Barbara L. Smith Data analysis and interpretation: Susan L. Troyan, Julia S. Wong, Carolyn M. Kaelin, Michele A. Gadd, Rebecca Gelman, Susan C. Lester, Stuart J. Schnitt, Dennis C. Sgroi, Barbara J. Silver, Jay R. Harris, Barbara L. Smith Manuscript writing: Julia S. Wong, Carolyn M. Kaelin, Rebecca Gelman, Barbara J. Silver, Jay R. Harris, Barbara L. Smith Final approval of manuscript: Julia S. Wong, Carolyn M. Kaelin, Susan L. Troyan, Michele A. Gadd, Rebecca Gelman, Susan C. Lester, Stuart J. Schnitt, Dennis C. Sgroi, Barbara J. Silver, Jay R. Harris, Barbara L. Smith

 

	Acknowledgment

 
We thank Stella Hetelekidis, MD, for her contributions to the conception of this study and her active participation in the early years of the trial.

	NOTES

 
Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, December 3-6, 2003, San Antonio, TX.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Fisher B, Costantino J, Redmond C, et al: Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 328:1581-1586, 1993[Abstract/Free Full Text]

2. Julien JP, Bijker N, Fentiman IS, et al: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: First results of the EORTC randomised phase III trial 10853—EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355:528-533, 2000[CrossRef][Medline]

3. Houghton J, George WD, Cuzick J, et al: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: Randomised controlled trial. Lancet 362:95-102, 2003[CrossRef][Medline]

4. Silverstein MJ, Poller DN, Waisman JR, et al: Prognostic classification of breast ductal carcinoma-in-situ. Lancet 345:1154-1157, 1995[CrossRef][Medline]

5. Silverstein MJ, Lagios MD, Groshen S, et al: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340:1455-1461, 1999[Abstract/Free Full Text]

6. Bijker N, Peterse JL, Duchateau L, 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 10853. J Clin Oncol 19:2263-2271, 2001[Abstract/Free Full Text]

7. Rampaul R, Valasiadou P, Pinder S, et al: Wide local excision with 10 mm clearance without radiotherapy for DCIS. Eur J Surg Oncol 27:788, 2001 (abstr 56)

8. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993-2000, 1999[CrossRef][Medline]

9. Fisher B, Land S, Mamounas E, et al: Prevention of invasive breast cancer in women with ductal carcinoma in situ: An update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28:400-418, 2001[CrossRef][Medline]

10. Allred D, Bryant J, Land S, et al: Estrogen receptor expression as a predictive marker of effectiveness of tamoxifen in the treatment of DCIS: Findings from NSABP B-24. Breast Cancer Res Treat 76:S36, 2002 (suppl 1; abstr 30)

11. Rakovitch E, Franssen E, Kim J, et al: A comparison of risk perception and psychological morbidity in women with ductal carcinoma in situ and early invasive breast cancer. Breast Cancer Res Treat 77:285-293, 2003[CrossRef][Medline]

Submitted June 14, 2005; accepted September 30, 2005.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, J. S. Articles by Smith, B. L. Search for Related Content PubMed PubMed Citation Articles by Wong, J. S. Articles by Smith, B. L. Related Articles Related Editorial