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Originally published as JCO Early Release 10.1200/JCO.2009.24.1489 on October 13 2009 © 2009 American Society of Clinical Oncology.
Clinical Dilemma of Ductal Carcinoma in SituDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Current management strategies for ductal carcinoma in situ (DCIS) range from mastectomy to excision plus radiation therapy (RT) to excision alone. This diverse spectrum of therapies reflects our inability to predict which DCIS will progress to invasive cancer or even which DCIS will recur when treated conservatively with excision alone. Therefore, the selection of the appropriate therapeutic approach for the individual patient with DCIS is a major dilemma. It is generally accepted that mastectomy is indicated when the size of the DCIS precludes complete excision with an acceptable cosmetic outcome; in addition, treatment with mastectomy results in local control and long-term survival in more than 95% of patients with DCIS.1 A survival benefit for RT after excision in patients with invasive breast cancer has been clearly established by the Early Breast Cancer Trialists' Collaborative Group meta-analysis,2 an important finding that changed the conceptual view of the role of local therapy in breast cancer management. Elimination of micrometastatic disease with systemic therapy has been considered the path to progress in invasive cancer, and the idea of improved survival with more aggressive local therapy, particularly for patients with node-positive disease, was counterintuitive to some clinicians. In contrast, DCIS is an entity for which micrometastases are not a consideration. Yet, the need for adding RT after excision to maintain local control in patients with DCIS has remained uncertain. Some of this controversy can be traced to favorable outcomes reported from retrospective, single-institution studies of highly selected patients with DCIS treated with excision alone who experienced low rates of local recurrence.3–5 These studies generated important questions regarding the need for RT in the conservative management of DCIS. Subsequently, four prospective randomized trials have shown an approximately 50% reduction in local recurrence when RT is added to excision.6–9 Within these trials, subset analyses failed to identify a group of patients who derived no benefit from RT based on favorable clinical/pathologic features (eg, older age, small lesion size, and low histologic grade). So why is the use of RT in DCIS controversial? First, none of the individual trials of breast-conserving surgery with and without RT showed a survival benefit for breast irradiation. However, the experience with invasive cancer provides a cautionary tale. For decades, it was believed that local recurrence did not affect long-term survival, and it required 15 years of follow-up and a substantial number of patients in randomized clinical trials for the survival implications of local recurrence in invasive cancer to become apparent.2 In DCIS, where there is no underlying force of mortality from systemic disease at the time of diagnosis, we believe that it is highly likely that an excess of invasive recurrences will ultimately have a small mortality impact. In this regard, it is noteworthy that a joint analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B17 and B24 trials, with 12 years of follow-up, demonstrated a doubling of the hazard ratio of death for women who experienced invasive local recurrences.10 However, critics of the randomized trials feel that inadequate attention was paid to defining the completeness of the excision carried out in those studies. Two studies (NSABP B177 and European Organisation for Research and Treatment of Cancer trial 108536) used a definition of negative margins as "tumor-filled ducts not touching ink." The United Kingdom trial suggested that this definition be used,9 and the Swedish DCIS trial,8 which used a wide resection, did not require clear margins of excision. Postexcision mammograms to document complete removal of calcifications were not required, and the extent of tissue processing was not specified. To many, these randomized trials demonstrated that with routine tissue processing and minimal negative margins, RT was beneficial in decreasing local recurrence but did not answer the question of whether a complete excision, as determined by a thorough pathologic and radiologic evaluation, could eliminate the need for RT. The retrospective work of Silverstein et al,11 in which patients treated with excision of a 1-cm margin of normal breast tissue and no RT had local control rates not statistically different from patients treated with excision and RT, regardless of the size or grade of DCIS, was seen as a validation of this concept. The simplicity of this approach was particularly attractive because it avoided the difficulties inherent in measuring the size of DCIS lesions in a reproducible fashion. In a recent population-based survey of surgeons, 21% advocated margins of 1 cm or more for the treatment of DCIS, even when RT was planned.12 It is with this background that the important first results of a prospective, single-arm, multi-institutional study (Intergroup CE5194) examining the role of excision alone in the treatment of DCIS appears in this issue of Journal of Clinical Oncology.13 This study tested the hypothesis that a more detailed pathologic assessment involving sequential sectioning and embedding of the complete specimen could determine truly negative margins and identify a group of DCIS patients who do not require breast irradiation. It is important to note that eligibility was restricted to patients with high-grade DCIS (defined as nuclear grade 3 with necrosis) between 3 and 10 mm in size and to patients with low- or intermediate-grade DCIS between 3 and 25 mm in size. Margins of at least 3 mm were required, and a postexcision mammogram was obtained for all participants. At a median follow-up of 6.7 years, the 5-year rate of an ipsilateral breast event (local recurrence) was 15.3% (95% CI, 8.2% to 22.5%) for the 105 eligible patients with high-grade DCIS. With a median follow-up of 6.2 years, the 5-year rate of an ipsilateral breast event (local recurrence) was 6.1% (95% CI, 4.1% to 8.2%) for the 565 eligible patients with low- or intermediate-grade DCIS. Invasive recurrence occurred in 53% of the low/intermediate-grade group and 35% of the high-grade group of patients who experienced recurrence. The authors concluded that, "rigorously evaluated and selected patients with low- to intermediate-grade DCIS with margins 3 mm or wider had an acceptably low rate of ipsilateral breast events at 5 years after excision without irradiation. Patients with high-grade lesions had a much higher rate, suggesting that excision alone is inadequate treatment."13 These important new findings raise at least two key questions regarding management of DCIS. The first is whether these results are practice changing. Or, in other words, should clinicians and patients currently recommending or receiving breast irradiation for DCIS with margins 3 mm or wider no longer do so? Because RT is already generally recommended after excision for high-grade DCIS, the high local recurrence rate observed in this study for high-grade DCIS will only strengthen that recommendation. The main question relates to the impact of these findings on low/intermediate-grade DCIS. The authors wisely note that, "the increase in ipsilateral breast events beyond 5 years warrants caution regarding the clinical implications of our results."13 Studies of patients treated with excision and RT have shown that although ipsilateral breast events are more common in high-grade DCIS than in low/intermediate-grade DCIS during the first 5 years, after 10 years of follow-up, ipsilateral breast event rates do not differ on the basis of grade.14 The annual hazard rate for ipsilateral breast events is fairly constant over the first 10 years after treatment in low/intermediate-grade DCIS, so one could anticipate the 10-year rate of ipsilateral breast events for the low/intermediate-grade group to be approximately 12%, with half being invasive. Experts may vary in their view on this, but our view is that longer follow-up is needed in the low/intermediate-grade group before the results should be considered practice changing. The second key question is: To which patients in the low/intermediate-grade group are these results applicable? The authors note that, "patients entered on this trial had a more favorable median lesion size and width of margins than the entry criteria required." The median lesion size for this group was only 6 mm (rather than the 25 mm allowed by the protocol), and only approximately a quarter of entered patients had lesions 10 mm or larger. Approximately two thirds of patients had margins greater than 5 mm, and approximately half of patients had margins greater than 10 mm (rather than the 3 mm allowed by the protocol). Also, the patients entered were generally older, with a median age of 60 years, and only 9% were younger than 45 years old. It is impossible at this time to assess the impact of adjuvant tamoxifen on the results. The authors provide an exploratory subset analysis using lesion size, margin width, age, and intent to use tamoxifen as variables, and none were significant in a Cox proportional hazards model. However, the sample size and event rate are too small to assure consistency of results across subsets. We believe it is important for clinicians and patients to keep in mind that entered patients were generally older than the usual median age of diagnosis of DCIS, had lesions smaller than 1 cm (on sequential sectioning and complete embedding), and had margins greater than 5 mm when evaluating the overall results. Therefore, these results may not be generalizable to the majority of patients with DCIS. In addition, the results of this study suggest that even in DCIS, the underlying biology of the disease, rather than the mechanics of the excision, will be the primary determinant of outcome. For the low/intermediate-grade group, there was no difference in the 5-year rate of local recurrence based on margins greater or less than 10 mm (6.7% and 5.6%, respectively). Within the size limits imposed by the eligibility criteria of the study, size also was not a predictor of local recurrence in the low/intermediate-grade group. Taken together, these observations indicate that the long-cherished concept that widely excised, small, low-grade DCIS lesions are least likely to recur is an overly simplistic notion. Just as there is a wide variation in the behavior of small low/intermediate-grade invasive cancers, the same seems to be true in DCIS. The challenge for the future is to identify markers that reliably predict behavior. The results of the Intergroup study presented in this issue are in agreement with the findings of a prospective, single-arm, multi-institution study from the Dana-Farber/Harvard Cancer Center.15 Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of no greater than 2.5 cm and final margins of at least 1 cm. Tamoxifen was not permitted. The accrual goal was 200 patients; in July 2002, the study closed to further accrual at 157 patients because the number of local recurrences met the stopping rules. With a median follow-up of 40 months, 13 patients had local recurrence as the first site of failure between 7 and 63 months. Another patient had ipsilateral local recurrence (DCIS) after a contralateral DCIS. The rate of ipsilateral local recurrence as first site of failure was 2.4% per patient-year (95% CI, 1.3% to 4.1% per patient-year), corresponding to a 5-year rate of 12.5%. Nine patients experienced recurrence with DCIS, and four had recurrence with invasive disease. These two studies indicate that even in the hands of experienced clinicians using defined protocols for surgery, mammographic evaluation, and tissue processing, patients with DCIS selected for treatment with excision alone using conventional clinical and pathologic features have a significant short-term risk of local recurrence. The study reported in this issue also provides insight into the management of women experiencing an in-breast recurrence after treatment with excision alone in the current era.13 Of the 62 women undergoing further surgery after local recurrence, 60% had a mastectomy. Whether this was a result of patient preference or medical necessity is not stated, but it is clear that avoidance of RT as part of initial treatment does not automatically translate into breast-conserving therapy for the majority of women after local recurrence. Minimizing the risk of recurrence is the single most important factor for most women when selecting local therapy for invasive or in situ breast carcinoma16; mastectomy is significantly more likely to be performed when the patient, rather than the surgeon, is the primary decision maker. In contrast, only 7.8% of patients with DCIS described great concerns about RT as a major factor in their choice of local therapy.17 The Intergroup trial published in this issue provides important information about the risks of local recurrence for a subset of patients with DCIS treated with excision alone, and the results can be used to educate comparable patients making a treatment decision. Because the study is not a randomized clinical trial, what it cannot tell us is what the reduction in the incidence of local recurrence in this highly favorable group of patients would be with the addition of RT. Finally, since the time that this trial was closed in 2002, patients with breast cancer, including those with DCIS, are increasingly choosing bilateral mastectomy as a management strategy.18 Although our understanding of which patients will develop local recurrence after excision alone remains imperfect, the major clinical dilemma in DCIS today may be trying to improve patient understanding of the risks and benefits of widely different therapeutic strategies for a disease that has almost no risk of mortality. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Jay R. Harris, Monica Morrow Financial support: Jay R. Harris, Monica Morrow Administrative support: Jay R. Harris, Monica Morrow Provision of study materials or patients: Jay R. Harris, Monica Morrow Collection and assembly of data: Jay R. Harris, Monica Morrow Data analysis and interpretation: Jay R. Harris, Monica Morrow Manuscript writing: Jay R. Harris, Monica Morrow Final approval of manuscript: Jay R. Harris, Monica Morrow
NOTES See accompanying article on page 5319 REFERENCES 1. Morrow M, Harris JR. Ductal carcinoma in situ and microinvasive carcinoma. J Harris, M Lippman, M Morrow, et al. Diseases of the Breast, ed 4 Philadelphia, PA: Lippincott Williams & Wilkins, 2009. 2. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087–2106, 2005.[Medline] 3. Lagios MD, Margolin FR, Westdahl PR, et al: Mammographically detected duct carcinoma in situ: Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 63:618–624, 1989.[CrossRef][Medline] 4. Schwartz GF, Finkel GC, Garcia JC, et al: Subclinical ductal carcinoma in situ of the breast: Treatment by local excision and surveillance alone. Cancer 70:2468–2474, 1992.[CrossRef][Medline] 5. Silverstein MJ, Lagios MD, Craig PH, et al: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77:2267–2274, 1996.[CrossRef][Medline] 6. 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 Group. J Clin Oncol 24:3381–3387, 2006. 7. 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] 8. 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 breast. J Clin Oncol 26:1247–1252, 2008. 9. 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] 10. Wapnir I, Dignam J, Julian TB, et al: Long-term outcomes after invasive breast tumor recurrence (IBTR) in women with DCIS in NSABP B-17 and B-24. J Clin Oncol 25:7s; 2007 (suppl 18S) abstr 520.[CrossRef] 11. 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. 12. Azu M, Abrahamse P, Katz SJ, et al: What is an adequate margin for breast conserving surgery (BCS)? Surgeon attitudes and correlates. Ann Surg Oncol 16:44; 2009 (suppl 1) abstr P45. 13. Hughes L, Wang M, 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 27:5319–5324, 2009. 14. Solin LJ, Kurtz J, Fourquet A, et al: Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol 14:754–763, 1996. 15. Wong JS, Kaelin CM, Troyan SL, et al: Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 24:1031–1036, 2006. 16. Katz SJ, Lantz PM, Janz NK, et al: Patient involvement in surgery treatment decisions for breast cancer. J Clin Oncol 23:5526–5533, 2005. 17. Katz SJ, Lantz PM, Janz NK, et al: Patterns and correlates of local therapy for women with ductal carcinoma-in-situ. J Clin Oncol 23:3001–3007, 2005. 18. Tuttle TM, Jarosek S, Habermann EB, et al: Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol 27:1362–1367, 2009.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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