Ann Surg Oncol (2013) 20:3175–3179 DOI 10.1245/s10434-013-3176-2
ORIGINAL ARTICLE – BREAST ONCOLOGY
DCIS Treated with Excision Alone Using the National Comprehensive Cancer Network (NCCN) Guidelines Patricia Wehner, MD1, Michael D. Lagios, MD2, and Melvin J. Silverstein, MD, FACS1 Breast Surgery, Hoag Memorial Hospital Presbyterian, University of Southern California, Los Angeles, CA; 2The Breast Cancer Consultation Service location, Boston, MA
1
ABSTRACT Background. In 2008, the NCCN published guidelines allowing low-risk DCIS patients to be treated by excision alone. The goal of this study was to determine local and distant recurrence and breast-cancer specific survival in patients with DCIS that meet NCCN criteria and are treated with excision alone. Methods. A prospective, single institution database was analyzed for patients with the following: pure ductal carcinoma in situ (no microinvasion), tumor extent 20 mm or less, age C50 years, margin width C2 mm, and nuclear grade 1 or 2 (non-high grade). Patients were treated with excision alone. Kaplan-Meier analysis was used to determine recurrence and survival rates. Results. A total of 205 patients were treated with excision alone. The median age was 59 years. The median time of follow-up was 51 months. The median extent of disease was 8 mm. There were a total of nine local recurrences. The 6-year probability of local recurrence was 6.6 %. The 12-year probability of local recurrence was 7.8 %. The 12-year breast cancer-specific survival probability was 100 %. Conclusions. The 12-year local recurrence rate for DCIS patients in NSABP Protocol B-17 treated with excision alone was 32 %, and for excision plus radiation therapy, it was 16 %. In this study, retrospectively applying the NCCN Guidelines to our patients, the 12-year local recurrence rate for excision alone was 7.8 %. Patients with
Ó Society of Surgical Oncology 2013 First Received: 12 April 2013; Published Online: 22 August 2013 P. Wehner, MD e-mail:
[email protected]
a low risk of local recurrence, if treated by excision alone, can be safely selected using the NCCN Guidelines.
Surgical management of ductal carcinoma in situ (DCIS) has evolved during the past 30 years. During the 1970s, most DCIS lesions were treated with mastectomy. During the 1980s, breast conservation, using lumpectomy and radiation therapy, was introduced for invasive breast cancer; however, the treatment of DCIS with breast conservation lagged. During the 1990s, breast conservation for DCIS was becoming the procedure of choice. Excision followed by radiation therapy was standard, but there were a few proponents of excision alone for selected cases.1–6 In 1993, the NSABP published the first prospective randomized trial of DCIS patients treated with excision alone or excision plus radiation therapy.7 DCIS patients who received postexcisional radiation therapy had a 50 % decrease in the risk of local recurrence at 5 years of follow-up. This trial established postexcisional radiation therapy as the standard of care for DCIS patients electing breast conservation. In 1996, the Van Nuys Prognostic Index was introduced in an attempt to select low-risk patients who might not benefit from radiation therapy.6 It used lesion size, margin width, nuclear grade, and the presence of necrosis to select patients for excision alone. In 2002, it was upgraded to include age and its name changed to the University of Southern California/Van Nuys Prognostic Index (USC/ VNPI).8,9 This allowed for a more accurate selection of patients appropriate for excision alone. In 2008, the National Comprehensive Care Network (NCCN) updated their recommendations on treatment of DCIS to include excision alone as an acceptable alternative to excision plus radiation therapy.10 This was the first nationally recognized organization to do so. The NCCN stated that factors that may determine local recurrence risk include: palpable mass, larger size, higher grade, close or
3176
involved margins, and age younger than 50 years. These factors were similar to those used in the USC/VNPI. In this study, we used NCCN recommendations to define a group of patients that fit the updated guidelines and to track their outcome following treatment by excision alone.11 METHODS A prospective database with a total of 5,751 patients was analyzed. We selected all patients who met the NCCN Guidelines for treatment of DCIS by excision alone. The inclusion criteria included: pure ductal carcinoma in situ (no microinvasion), tumor extent 20 mm or less, age 50 years or older, margin width C2 mm, and nuclear grade 1 or 2 (non-high grade). All patients were treated with excision alone. No adjuvant hormonal, systemic, or radiation therapy was used in conjunction with surgery for any patient. Treatment was not randomized. Patient preference, after full disclosure and discussion of available data, was the major factor in the treatment selection. Every effort was made to excise all lesions completely. Localization by bracketing needles, intraoperative radiography of the specimen, and correlation with the preoperative mammogram were performed in every case involving a nonpalpable tumor. Margins were inked or color-coded either in the pathology department or operating room by the surgeon. Radiopaque markers were applied by the surgeon in every case for radiologic and pathologic orientation. Tissue sections were arranged and evaluated in sequence as described by Lester et al.12 Pathologic evaluation included histological subtype, nuclear grade, margin width, and the maximal extent of the lesion, using threedimensional reconstruction. Margin width was determined by direct measurement or ocular micrometry. It was defined as the smallest distance between edge of tumor and an inked margin. Margins greater than 10 mm were recorded as 10 mm or more. Margins in patients who underwent reexcision and in whom no additional DCIS was found were reported as being 10 mm in width. KaplanMeier analysis was used to determine the probability of local disease-free recurrence and breast cancer-specific survival. RESULTS A total of 1,689 patients with the diagnosis of DCIS were identified; 267 of these patients met the NCCN criteria for excision alone as stated above, and 62 of these patients elected to be treated with adjuvant radiation therapy. In total, 205 patients were treated with excision alone and are the focus of this paper. No patient received
P. Wehner et al.
adjuvant hormonal or systemic therapy. Patient characteristics and recurrence rates are detailed in Table 1. The median age was 59 (range 50–84) years. The median time of follow-up was 51 (range 6–268) months for excision alone patients and 131 (range 7–310) months for excision plus radiation therapy patients. The median extent of disease was 8.0 (range 1–20) mm. DCIS was generally excised in an elliptical fashion. The median size of the excision specimens was 45 mm with a median weight of 56 g. A total of 119 patients had a minimum margin width of 10 mm or more. The median margin width cannot be precisely stated, because patients with 10 mm or more margins were scored as having 10-mm margins. Analysis for estrogen and progesterone receptors in patients with DCIS was not commonly performed before the later 1990s when it became available by immunohistochemical methods. Both tests were available for 75 patients in this series. Seventy-two of 75 (96 %) were estrogen receptor-positive and 62 of 75 (83 %) were progesterone-positive. There were nine local recurrences in patients treated with excision alone: four invasive and five DCIS. The median time to local recurrence was 54 months. Eight of nine patients with local recurrences had margin widths of 10 mm or more. Eight of nine patients had a recurrence at or near the index tumor. One recurrence was in a different quadrant of the ipsilateral breast, likely representing a new lesion. One patient with a local invasive recurrence developed metastatic disease. Of the nine patients with local recurrence, five elected to be treated with reexcision and radiation therapy. Four elected conversion to mastectomy. The 6-year probability of local recurrence was 6.6 %. The
TABLE 1 Patient characteristics and recurrence rate for the 205 patients who met NCCN criteria and were treated by excision alone Number of patients
205
Median age
59
Median follow-up Average time of follow-up
51 mo 67 mo
Median disease size
8.0 mm
Median specimen size
45 mm
Median margin width
[10 mm
% Estrogen receptor positive
96 %
% Progesterone receptor positive
83 %
Number of ipsilateral invasive recurrences
4
Number of ipsilateral DCIS recurrences
5
Number of distant recurrences
1
6-year local recurrence probability
6.6 %
12-year local recurrence probability
7.8 %
12-year breast cancer specific survival
100 %
DCIS Treated with Excision Alone Using NCCN
3177
Probability
P = 0.001
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
2
10
12
Years
FIG. 1 Local recurrence-free for 205 patients who met the NCCN criteria and were treated by excision alone. It reveals a local recurrence probability of 7.8 % at 12 years
12-year probability of local recurrence was 7.8 % (Fig. 1). The 12-year breast cancer-specific survival probability was 100 %. The median time to local recurrence was 4.7 years with the shortest time to recurrence 1.8 years and the longest 9 years. DISCUSSION Local management of DCIS includes mastectomy, excision with radiation therapy, and excision alone. Mastectomy is required for patients with lesions too large to excise with an acceptable cosmetic result and for those with true multicentric disease. It also may be the best choice for patients previously excised but in whom final pathology reveals involved margins and for whom reexcision cannot be successfully performed or who have poor cosmesis after excision. Mastectomy is generally advised for patients with a local recurrence after previous excision and radiation therapy and for patients who are BRCA positive. During the past 20 years, a heavily debated topic has been whether all patients treated with breast conservation require breast irradiation after excision. The NSABP B-17 trial was the first randomized, controlled trial that treated DCIS patients with breast conservation therapy alone. NSABP B-17 assigned 818 patients with localized DCIS to excision alone or excision followed by radiation therapy. The 12-year local recurrence rate for DCIS patients treated with excision alone was 32 % and for excision plus radiation therapy, it was 16 %, a statistically significant difference.13–15 This trial established postexcisional radiation therapy as the standard of care for patients with DCIS treated conservatively.
In 2007, a meta-analysis was published, comparing four randomized DCIS trials, all of which had an excision alone arm and excision plus radiation therapy arm.16 Overall, there was an approximate 60 % reduction in local invasive and noninvasive recurrence for patients who received radiation therapy compared with patients treated with excision alone. There was, however, no decrease in distant recurrence or breast cancer mortality for patients who received radiation therapy, in spite of a lower local recurrence rate. In 2010, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) also published a meta-analysis comparing four randomized DCIS trials. They concluded that radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event by 15.2 %. Again, there was no significant effect on breast cancer mortality.17 In 2011, the NSABP B-17 published a 15-year update of their DCIS trials.15 The ipsilateral breast tumor recurrence rate for patients treated with lumpectomy alone at 15 years was 35 %. For those patients treated with lumpectomy plus radiation, it was 19.8 %. Radiation therapy approximately halved the IBTR at 15 years, but again the breast cancer mortality rate was the same. During the past 20 years, many papers have been published arguing against overtreatment of DCIS with radiation therapy.3,8,18–21 Lagios et al. were early proponents of excision alone. They reported a 9 % local recurrence rate at 12-year median follow-up for patients with low-grade DCIS, 25 mm or smaller, discovered mammographically and excised with 1 mm or greater margins.22,23 Silverstein et al.5 suggested that margin width could be used by itself to select patients for excision alone. For 133 patients with margin widths of 10 mm or more, there was no significant benefit from radiation therapy. In 2002, using margin width, DCIS size, patient age, and a combination nuclear grade and necrosis (USC/VNPI [University of Southern California/Van Nuys Prognostic Index]), it was possible to select patients with a 12-year probability of local recurrence of 6 % or less after treatment by excision alone.8,24 Historic DCIS trials are problematic, because none of the randomized trials of DCIS treated with excision alone versus excision plus radiation therapy were empowered to determine size and margin status as detailed in our studies and as described by Lester et al.12 We have always used a rigorous pathologic evaluation to determine tumor size and margin status. We feel that this is important to lower recurrence rates in this subset of patients. The Eastern Cooperative Oncology Group (ECOG) Study 5,194 (E5194) prospectively defined a low-risk subset of DCIS patients in whom radiation after lumpectomy could potentially be omitted.25 There were two arms of the study: low/intermediate-grade DCIS, B25 mm in
3178
size, and high-grade DCIS, B10 mm in size. All patients in both arms had to have 3 mm or greater margins. The ECOG trial showed that for patients with low or intermediate grade DCIS, the 5- and 7-year ipsilateral breast tumor recurrence (IBTR) rate was 6.1 % and 10.5 % respectively. They suggested that excision alone could be an adequate treatment for this subgroup of patients. There are some differences between the ECOG low-risk group and our excision alone patients. ECOG allowed patients aged 18 years or more; we required that they be 50 years or more. ECOG required 3-mm margins; we required 2-mm margins. ECOG allowed tumors to be up to 25 mm in extent; we allowed up to 20 mm in extent. Overall, both groups were highly favorable and did similarly. Our study is a nonrandomized series of excision alone patients who retrospectively met a set of criteria established by the NCCN establishing them as patients at low risk of recurrence, if treated by excision without the addition of radiation therapy. With a median extent of resection of 45 mm, a median weight of 56 g for each resection, and a median margin width of 10 mm or more, these patients were well excised. In our opinion, the number of patients with wide margin widths contributes to our low local recurrence rate, but it is not the whole answer because 8 of 9 patients with local recurrences had margin widths of 10 mm or more. Non-high grade, small tumor size, and older age also are important contributors to a low local recurrence. When the decision was made not to pursue adjuvant radiation treatment, we believed the patient was at a low risk of recurrence due to their favorable tumor markers, size of disease, and extent of resection even though there was no level 1 evidence to support this decision. The leading factor in the decision not to treat with radiation therapy, however, was patient driven. In the early years, most patients meeting the NCCN criteria elected adjuvant radiation therapy because that was standard at the time. During the more recent year, most patients meeting the NCCN criteria elected excision alone, explaining the much longer follow-up times for excision plus radiation therapy patients. The patients entered into this database were highly motivated and chose quality of life and cosmesis over a lower recurrence rate associated with radiation therapy. Their plan was to have close clinical follow-up. Of the 62 patients that met the NCCN criteria and chose to be treated with adjuvant radiation therapy, there were no same quadrant recurrences. The overall breast cancer mortality rate was the same for those treated with radiation therapy vs. those treated without radiation therapy, zero. Radiation therapy is time-consuming, expensive, and is associated with a range of side effects, including potentially lethal cardiac consequences. Darby et al. 26,27 confirmed an increased risk of ischemic heart disease in
P. Wehner et al.
women who received radiation therapy as part of their treatment for breast cancer. In addition, radiation therapy has various local side effects, including dermatitis, skin burns, and fibrosis. Radiation benefit is limited to local control; there is no survival advantage in patients with DCIS.16,17 The addition of whole breast radiation also removes the ability to further treat patients with lumpectomy if a recurrence were to develop. If there is no difference in survival, regardless of treatment and radiation therapy costs time, money, and has significant side effects, why not try to select low-risk patients for treatment with excision alone? That is what we attempted to do in this study. Patients who met the NCCN guidelines as low risk and who were treated with excision alone had a 7.8 % risk of local recurrence at 12 years of follow-up and no risk of dying from breast cancer during the same time period. CONCLUSIONS The NCCN guidelines may be used to help identify a subset of patients who are appropriate for treatment with excision alone. Those patients have small, non-high-grade DCIS lesions with margins C2 mm. The lesions are 20 mm or less in extent and the patients are age 50 years or older. Patients who meet all of those criteria have a less than 8 % chance of local recurrence at 12 years when treated with excision alone. If radiation therapy had been added, the recurrence rate would have dropped by 50–60 % to approximately 3–4 %. To achieve this small absolute benefit, 100 patients would have to have been irradiated; 92 would have received no benefit, whereas 3–4 would receive a local control benefit. There is no evidence that these patients would have received a survival benefit. We believe these numbers are sufficiently low that radiation therapy is not required for these patients. For the small number of patients who developed a local recurrence, most can be treated with reexcision with or without radiation therapy at the time of recurrence. REFERENCES 1. Lagios M, Page D, Silverstein M. Prospective study of wide excision alone for ductal carcinoma in situ of the breast [comment]. J Clin Oncol. 2006;24:3809-11. 2. Lagios MD. Duct carcinoma in situ: pathology and treatment. Surg Clin N Am. 1990;70:853-71. 3. Schwartz G. The role of excision and surveillance alone in subclinical DCIS of the breast. Oncology. 1994;8(2):21-6. 4. Schwartz G, Finkel G, Carcia J, Patchefsky A. Subclinical ductal carcinoma in situ of the breast: treatment by local excision and surveillance alone. Cancer. 1992;70:2468-74. 5. Silverstein MJ, Lagios M, Groshen S, et al. The influence of margin width on local control in patients with ductal carcinoma in situ (DCIS) of the breast. New Engl J Med. 1999;340:1455-61.
DCIS Treated with Excision Alone Using NCCN 6. Silverstein MJ, Poller D, Craig P, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer. 1996;77:2267-74. 7. 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. 1993;328:1581-6. 8. Silverstein MJ. The University of Southern California / Van Nuys Prognostic Index for ductal carcinoma in situ of the breast. Am J Surg. 2003;186:337-43. 9. Silverstein MJ, Lagios M, Recht A, eds. Ductal carcinoma in situ of the breast, 2nd edn. Philadelphia: Lippincott Williams & Wilkins; 2002. 10. Carlson RW, Allred DC, Anderson BO, et al. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. 2008; www. nccn.org, 2008. 11. Therialt RT, Carlson RW, Allred C, et al. NCCN Guidelines Breast Version 2.2013. Breast Cancer. 2013; www.NCCN.org. 12. Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Arch Pathol Lab Med. 2009;133(1):15-25. 13. Fisher B, Redmond C, ER F. Radiation therapy for in situ or localized breast cancer: the authors reply. N Engl J Med. 1993; 329:1578. 14. Fisher E, Dignam J, Tan-Chie E, et al. Pathologic findings from the National Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer. 1999;86:42938. 15. Wapnir I, Dignam J, 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 DCIS. J Natl Cancer Inst. 2011;103(6):478-88. 16. 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 trials. Radiation Oncol. 2007;2:28-39. 17. (EBCTCG) EBCTCG. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Monogr. 2010;41:162-77.
3179 18. Lagios M, Margolin F, Westdahl P, Rose N. Mammographically detected duct carcinoma in situ. Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer. 1989;63:619-24. 19. Lagios M, Westdahl P, Margolin F, Rose M. Duct Carcinoma in situ: Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer. 1982;50: 1309-14. 20. Schwartz G, Patchefsky A, Finkelstein S, et al. Nonpalpable in situ ductal carcinoma of the breast. Arch Surg. 1989;124:2932. 21. Silverstein MJ. An argument against routine use of radiotherapy for ductal carcinoma in situ. Oncology. 2003;17(11):1511-46. 22. Lagios M. Controversies in diagnosis, biology, and treatment. Breast J. 1995;1:68-78. 23. Lagios M. The Lagios experience. In: Silverstein MJ, Recht A, Lagios M, eds. Ductal carcinoma in situ of the breast, 2nd edn. Philadelphia: Lippincott Williams & Wilkins; 2002:303-7. 24. Silverstein MJ, Epstein M, Sposto R. Predicting local recurrence in patients with DCIS. In: Silverstein MJ, Recht A, Lagios M, eds. Ductal carcinoma in situ of the breast, 2nd edn. Philadelphia: Lippincott Williams & Wilkins; 2002. 25. Hughes L, Molin W, Page D, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27(32): 5319-24. 26. Darby S, McGale P, Taylor C, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women un US SEER cancer registries. Lancet Oncol. 2005;6:557-65. 27. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987-98.
