Originally published as JCO Early Release 10.1200/JCO.2007.12.7969 on February 4 2008

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Absolute Risk Reductions for Local Recurrence After Postoperative Radiotherapy After Sector Resection for Ductal Carcinoma In Situ of the Breast

Lars Holmberg, Hans Garmo, Bengt Granstrand, Anita Ringberg, Lars-Gunnar Arnesson, Kerstin Sandelin, Per Karlsson, Harald Anderson, Stefan Emdin

From the Department of Surgical Sciences and Regional Oncologic Center, Uppsala University Hospital, Uppsala; Department of Plastic and Reconstructive Surgery, University Hospital MAS, Malmö; Department of Surgery, University Hospital, Linköping; Department of Surgery, Karolinska University Hospital, Stockholm; Department of Oncology, Sahlgrenska University Hospital, Gothenburg; Department of Cancer Epidemiology, Lund University, Lund; Sweden Department of Surgery, Umeå University Hospital, Umeå, Sweden; and King's College London, Division of Cancer Studies, London, United Kingdom

Corresponding author: Lars Holmberg, MD, PhD, Division of Cancer Studies, Thomas Guy House, 3rd Floor, King's College London, Guy's Campus, London SE1 9RT, United Kingdom; e-mail: lars.holmberg{at}kcl.ac.uk

	ABSTRACT

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Purpose Evaluate the effects of radiotherapy after sector resection for ductal carcinoma in situ of the breast (DCIS) in patient groups as defined by age, size of the lesion, focality, completeness of excision and mode of detection.

Patients and Methods A total of 1,067 women in Sweden were randomly assigned to either postoperative radiotherapy (RT) or control from 1987 to 1999, and 1,046 were followed for a mean of 8 years. The main outcome was new ipsilateral breast cancer events and distant metastasis–free survival analyzed according to intention to treat.

Results There were 64 ipsilateral events in the RT arm and 141 in the control group corresponding to a risk reduction of 16.0 percentage points at 10 years (95% CI, 10.3% to 21.6%) and a relative risk of 0.40 (95% CI, 0.30 to 0.54). There was no statistically significant difference in distant metastasis–free survival. There was an effect modification by age, yielding a low effect of RT in women younger than 50, but substantial protection in women older than 60 years. The age effect was not confounded by focality, lesion size, completeness of excision, or detection mode. There was no group as defined by our stratification variables that had a low risk without radiotherapy.

Conclusion Our results indicate that younger women have a low protective effect of conventional RT after sector resection. Older women benefit substantially. We caution that the age effect was seen in a subgroup analysis. Further search with conventional clinical variables for a low risk group that does not need RT does not seem fruitful.

	INTRODUCTION

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In making up the balance between effective protection for local recurrence on one hand and negative long-term adverse effects, overtreatment, and need to consider alternative use of limited radiotherapy resources on the other, one question in the management of ductal carcinoma in situ (DCIS) is to optimize the use of postoperative radiotherapy after sector resection. There is no randomized evidence to define a low-risk group where radiotherapy (RT) could be abandoned safely.^1-5 Still, the question remains of whether there are patient groups where RT is more or less effective in terms of absolute risk reduction. Answers to that question have relevance for a number of clinical decisions after local excision of DCIS and for questions to be asked in clinical studies: Are there patient groups where boost or additional medical therapy is needed to diminish the risk of local recurrence? In groups with low RT efficacy, does the surgical intervention need to be more radical, or is there a group hitherto treated with breast conservation, where women would have better results with mastectomy followed by reconstruction?

This article reports the results from a mean follow-up of 8.4 years of 1,046 women randomly assigned in Sweden to RT or control only after sector resection of DCIS, adding 3 years to our previous publication.⁵ Further, we aimed to study the efficacy of RT after long-term follow-up in subgroups defined by age at diagnosis, size of the lesion, focality, completeness of excision and mode of detection (screening v no screening). The main measure of effect was the absolute risk reduction of the cumulative incidence proportion of local recurrence.

	PATIENTS AND METHODS

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Enrollment and Random Assignment
Women who underwent breast-conserving surgery for histologically proven DCIS occupying a quadrant or less of the breast and with a clinically negative examination of the axilla were eligible. Paget's disease of the nipple, invasive carcinoma or intracystic carcinoma in situ, ongoing pregnancy, history of previous or concurrent malignancy (except basal cell carcinoma and treated carcinoma in situ of the uterine cervix) were exclusion criteria. Women were randomly assigned to RT or to control after full informed consent. Allocation to the two study arms was given to the treating physician via telephone from one of six regional oncologic centers in Sweden. The trial was nationwide, and randomization was stratified for health care region. Baseline data were reported by the treating physician. The study was approved by the regional ethics committees.

Interventions
Patients underwent a sector resection and macroscopic lateral and medial margins of at least one centimeter were aimed for. Specimen x-ray was compulsory. Histopathology was based on routine reports. Microscopically radical removal of the lesion was not required, and the study protocol stated that, "due to the multicentric nature of DCIS ‘microscopic radicality’ cannot always be achieved." Radical removal of the DCIS was finally judged by the operating surgeon on the basis of operative findings, specimen radiography, and pathology report.

RT was administered in the supine position. The target volume was the remaining breast parenchyma as defined by palpation, the position of the surgical scars and available radiographs. The specification of the absorbed dose was according to the International Commission on Radiation Units Report 50.⁶ The protocol allowed the treatment to be administered either continuously or as a split-course treatment. However, none of the centers used split course as a routine, and it was used in only a few women (< 50 patients in the whole study) according to their personal preference. The specification dose was 50 Gy administered in 25 fractions over 5 weeks or 54 Gy administered in two series with a gap of 2 weeks corresponding to a biological effective dose value of 46 Gy for the tumor. Wedges were used to compensate the dose to the breast. The dose in the specification point should be 15.5 according to International Commission on Radiation Units formulation, according to the protocol (which should be used to correct for departures of doses or overall time). Blocking of the heart was not employed.

Measurement and Definition of Tumor Characteristics
There was no formal prospective histopathologic study protocol. The information in this report is based on a monitoring of all medical records during 2005 and 2006 regarding clinical findings, mammography reports, operative findings, specimen x-rays, histopathologic reports, and deliberations of clinicians serving on tumor boards documented in the records. For classification of tumor size, multifocality, completeness of excision, and mode of detection, we used a hierarchy where written statements in histopathology reports and mammography reports had priority (in that order) over other statements (such as written documentation on why women were offered to participate in the trial or other clinical decisions) in the records. For multifocality, we defined all those as unifocal where there was clear documentation of unifocality. Those with evidence of multifocality, multicentricity or unclear status were defined as nonunifocal. For a complete excision, we demanded clear evidence that the whole radiographic or clinical lesion was excised as documented by histopathology, specimen radiography, and findings at the first postoperative mammography. This group was compared with those with clear histopathologic involvement of margins, radiographic signs of incomplete excision, or unclear documentation of the completeness of the excision.

Follow-Up and Definitions of Events
Patients were initially followed by biannual clinical examination and yearly mammography for 5 years, and thereafter by clinical examination and mammography on a yearly basis. For the purpose of this report, we used the afore-described monitoring of all patients records, and we documented events up to July 31, 2005. We also searched computerized inpatient, mammography, and pathologic laboratory registers for indications of any recurrence in the patient cohort.

All recordings of events in the ipsi- or contralateral breast or in the ipsilateral axilla were based on clinical findings or mammography and further verified by histology. They were classified as either in situ or invasive carcinoma. Distant metastases were diagnosed by scintigram, radiographs, or computed tomographic scans. When findings with imaging techniques were doubtful, microscopic confirmation was performed if possible. Lymph node metastases beyond the axilla were confirmed by fine-needle aspiration cytology.

Statistical Methods
Absolute risks of ipsilateral breast recurrence were calculated by means of cumulative incidence curves⁷ with distant recurrence and death as competing events. Events of contralateral cancer were ignored in the analyses, and time was censored at end of follow-up. Proportional hazards models were determined for the subdistribution of ipsilateral breast recurrence,⁸ and relative hazards were used as the estimator of relative risk (RR) of the effect of RT estimated for subgroups of patients taking the competing events into account. Interactions between effect of RT and prognostic factors were tested using likelihood ratio tests.

All analyses were performed according to the intention-to-treat principle, and all CIs and significance tests were two-sided.

	RESULTS

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Participants
The consort diagram (Fig 1) of the study has been described earlier in detail.⁵ Between September 1987 and December 31, 1999, 1,067 patients were randomly assigned to either RT (n = 534) or control (n = 533). Twenty-one patients were excluded because of protocol violations documented on the basis of information available at the time of random assignment, leaving 526 women evaluated in the RT arm and 520 in the control arm. Forty-two of those allocated to RT did not receive RT, and five patients allocated to control received RT for different reasons. No patient was lost to follow-up (Fig 1).

View larger version (44K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Consort diagram of patient flow. LCIS, lobular carcinoma in situ. Reasons in light blue and brown boxes refer to reasons for noncompliance.

Baseline Characteristics by Study Arm and Overall Result
Patient characteristics are descried in Table 1. One fourth of the patients (252 of 1,046) were younger than 50. Approximately 20% of the women had a tumor size less than 10 mm. Only 11% of the patients had clearly histopathologically involved margins, and 9% had unclear documentation regarding the completeness of removal of the index lesion as judged by monitoring the medical records. Approximately 8% of the patients in each arm had clearly multifocal tumors, and few had multicentric tumors. Eighty-four percent were judged unifocal. More than three quarters of the patients had a screening-detected lesion.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Cumulative incidence proportion of new ipsilateral breast events according to randomization arm (RT v control). RT, radiotherapy.

RT Effect by Age and in a Tentative Low-Risk Group
Because of the indications of an interaction between age and the effect of RT, we further explored the difference in 8-year cumulative incidence proportion between the control and RT (Fig 3). We show 8-year results because a reasonable number of women in each subgroup were observed at that time. The results extended to 10 years are, however, similar (Fig 4A). There was a similar cumulative incidence in the control group over the ages, varying between 24% and 31%, being 26% among those younger than 50. However, there was an increasing effect of RT with age. The cumulative incidence in the RT arm was 20% in the youngest age group, falling to 8% among those age 65 and older. There was thus a modest absolute risk reduction in younger women (6%) and a substantial reduction (18%) in older women (Fig 3).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Influence of age on 8-year cumulative incidence proportion of ipsilateral breast events. The estimates are for the same age groups as depicted in Table 2. RT, radiotherapy.

View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Cumulative incidence proportion of new ipsilateral breast events by randomization arm for (A) the low-effect group (age < 50 years) and (B) the low-risk group (size of lesion 10 mm, complete excision, and unifocal). RT, radiotherapy.

We could not substantiate that any of our strata constituted a low-risk group. All estimates of cumulative incidence proportions in the control arms defined by tentatively good prognostic characteristics (tumor size < 10 mm, unifocality, complete excision, and screening detection) indicate a risk around 2% per year and higher (17.9%, 24.4%, 26.7%. and 23.0% at 8 years respectively). However, since there theoretically could be a combination of factors entailing a low risk also without RT, we combined these tentatively good prognostic factors to a low-risk group (screening detection and tumor size were highly correlated, so only tumor size was included of the two). The cumulative incidence proportion curves by randomization arm are shown in Figure 4B. Even after combination of these factors, the control group levels in cumulative incidence proportion passed 10% at 4 years in the putative low-risk group. There was a protective effect from RT also in this subset (Fig 4B).

	DISCUSSION

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RT substantially reduces the risk of local recurrence after a sector resection for DCIS. Analyzing strata defined by age, tumor size, completeness of excision, focality of the primary lesion, or detection mode, we found an interaction by age and effect of RT indicating a lower effect of RT in the young. In women younger than 50, this interaction resulted both in a small absolute risk reduction after RT and a cumulative incidence of more than 1% per year even in those randomly assigned to RT. We could not define a group of women not administered RT having less than 1% local recurrence risk per year. There was no statistically significant difference in distant metastasis–free survival between the two study arms. The follow-up is too short to inform about risk of contralateral cancer with or without RT.

All analyses are based on the randomized design. The follow-up was complete. We monitored all original records, computerized mammography, and inpatient registries, and there is little probability that we missed new breast cancer events in either study arm. We used the cumulative incidence proportion, which takes competing risks into account. The compliance to recommended therapy was high, with a total of only 47 noncompliers.

We based our definitions of subgroups on routine examinations at the time of diagnosis. Thus, the results should be generalizable to a broad clinical practice. Our retrospective definition of focality and completeness of excision entail misclassification and, for example, we cannot study the influence of clear or involved margins with the same precision as in a prospective study. However, the misclassification of lesion size, completeness of excision, and focality during the years of recruitment is not related to future risk of recurrence and is thus nondifferential. The nondifferential misclassification may dilute differences between comparison groups. Thus, specialist teams that prospectively collect detailed information may do a better prognostication and prediction than what we demonstrate.^10,11

Subgroup analyses should be interpreted cautiously. The risks of finding random differences, low power to detect a modest but clinically relevant difference, and an undue emphasis on the special characteristics of the data set always ensue. Our analyses used precontemplated subgroups before data were seen, and we thus avoided data dredging. We avoided the problem of mass significance by not relying on significance testing in our interpretation. Our subgroup results cannot be taken as a basis for clinical recommendations, but points to domains where new important trials can be made. The correctness of the routine diagnosis on 271 randomly selected specimens were of the same magnitude as in other, similar trials.^12,13

Other studies have implicated young age as a risk factor of recurrence after breast conservation for DCIS. However, our study implicates that this may be a problem of less responsiveness to RT rather than a basically higher risk.^14,15 Boost was not used, and boost may add substantially to the effect.¹⁶ In our previous study of histopathologic risk factors,⁹ age was not a modifier of the impact of tumor characteristics on the risk of local recurrence. For the purpose of the present report, we also checked presence of necrosis by age in the sampled subcohort in the histopathologic study, and it was similar in the age groups, varying between 70% and 80% and highest in the 58-to-64 age group. Thus, the age effect was not explained by a confounding from histopathologic characteristics. Our findings may indicate an appropriate age group for further studies where, for example, RT is combined with other adjuvant therapies.

Although other investigators have studied the age effect mainly in relation to RT in the perspective of the young woman (younger than 40 years),^4,15 our results with a large age span show that RT has a substantial effect in women age 60 and older. A 70-year-old woman in the industrialized world has a long life expectancy (eg, in Sweden today, 16.5 years). RT can save most from the medical and psychosocial burden of a cancer recurrence during the remaining years of life. A higher age per se is thus not a rational contraindication for postoperative RT. Our results by age are not likely to be confounded by use of exogenous hormones or hormonal therapy. Hormone-replacement therapy was considered strictly contraindicated in all women with a previous breast cancer in situ at the time in Sweden. The use of tamoxifen was less than 4% in our study cohort.⁵ None of the women underwent hormonal ablation.

Not even in a population offered an effective population-based screening program capable of lowering breast cancer mortality¹⁷ were we able to find subsets with acceptably low local recurrence rates after surgery only. An effective screening program also indicates high standards of clinical mammography. A standardized sector resection and frequent use of specimen radiography did not remove the need for postoperative RT either.

Our results point to several research areas. There are groups of women for whom there is a need to make protection against local recurrence of DCIS after breast conservation more effective. That this group so far probably is best defined by young age with a long expected survival time makes the question important, because the risk of recurrence also involves risk of an invasive tumor. Our results, together with those reported by others, underline that it is not fruitful to search with common clinical markers for a group where RT can be omitted.¹ However, the search for markers of risk and of responsiveness to RT must continue on a detailed level of tumor biology.¹⁸ There is still a need to avoid radiation in those who do not benefit to prevent long-term adverse effects and because of the need to consider alternative use of RT resources with an increasing incidence of cancer in an aging world population. We need to allocate RT resources to instances where benefits are high in terms of saving years of life or avoiding severe symptoms.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Lars Holmberg, Anita Ringberg, Lars-Gunnar Arnesson, Harald Anderson, Stefan Emdin

Financial support: Lars Holmberg, Anita Ringberg, Stefan Emdin

Administrative support: Lars Holmberg, Lars-Gunnar Arnesson, Kerstin Sandelin, Per Karlsson, Stefan Emdin

Provision of study materials or patients: Lars Holmberg, Bengt Granstrand, Anita Ringberg, Lars-Gunnar Arnesson, Kerstin Sandelin, Per Karlsson, Stefan Emdin

Collection and assembly of data: Lars Holmberg, Hans Garmo, Bengt Granstrand, Anita Ringberg, Lars-Gunnar Arnesson, Kerstin Sandelin, Per Karlsson, Stefan Emdin

Data analysis and interpretation: Lars Holmberg, Hans Garmo, Bengt Granstrand, Anita Ringberg, Lars-Gunnar Arnesson, Kerstin Sandelin, Per Karlsson, Harald Anderson, Stefan Emdin

Manuscript writing: Lars Holmberg, Hans Garmo, Bengt Granstrand, Per Karlsson, Harald Anderson, Stefan Emdin

Final approval of manuscript: Lars Holmberg, Hans Garmo, Bengt Granstrand, Anita Ringberg, Lars-Gunnar Arnesson, Kerstin Sandelin, Per Karlsson, Harald Anderson, Stefan Emdin

	NOTES

 
published online ahead of print at www.jco.org on February 4, 2008.

Supported by the Swedish Cancer Society. This study was governed by the Swedish Breast Cancer Group.

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

	REFERENCES

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1. Mokbel K, Cutuli B: Heterogeneity of ductal carcinoma in situ and its effects on management. Lancet Oncol 7:756-765, 2006[CrossRef][Medline]

2. Fisher B, Lande 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]

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. Bijker N, Meijnen P, Peterse LJ, 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. J Clin Oncol 24:3381-3387, 2006[Abstract/Free Full Text]

5. Emdin SO, Granstrand B, Ringberg A, et al: Radiotherapy after sector resection for ductal carcinoma in situ of the breast: Results of a randomised trial in a population offered mammography screening. Acta Oncol 45:536-543, 2006[CrossRef][Medline]

6. ICRU: Prescribing and Reporting Photon Beam Therapy, Report #50. Washington, DC, International Commission on Radiation Units and Measurements, 1993

7. Kalbfleisch DL, Prentice RL: The statistical analysis of failure time data. New York, NY, John Wiley, 2002, pp 252-258

8. Fine JP, Gray RJ: A proportional hazards model for the subdistribution of a competing risk. JASA 94:496-509, 1999

9. 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 trial. Eur J Cancer 43:291-298, 2007[CrossRef][Medline]

10. Silverstein MJ: The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg 186:337-343, 2003[CrossRef][Medline]

11. Macdonald HR, Silverstein MJ, Lee LA, et al: Margin width as the sole determinant of local recurrence after breast conservation in patients with ductal carcinoma in situ of the breast. Am J Surg 192:420-422, 2006[CrossRef][Medline]

12. Fisher ER, Costantino J, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project protocol B-17. Cancer 75:1310-1319, 1995[CrossRef][Medline]

13. 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]

14. 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 breast. Cancer 103:1137-1146, 2005[CrossRef][Medline]

15. Cutuli B, Cohen-Solal-le Nir C, de Lafontan B, et al: Breast-conserving therapy for ductal carcinoma in situ of the breast: The French Cancer Centers’ experience. Int J Radiat Oncol Biol Phys 53:868-879, 2002[CrossRef][Medline]

16. 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 Network. Lancet Oncol 7:652-656, 2006[CrossRef][Medline]

17. The Swedish Organised Service Screening Evaluation Group: Reduction in breast cancer mortality from organised service screening with mammography: 1, Further confirmation with extended data. Cancer Epidemiol Biomarkers Prev 15:45-51, 2006[Abstract/Free Full Text]

18. Nuyten DS, Kreike B, Hart AA, et al: Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 8:R62, 2006[CrossRef][Medline]

Submitted May 25, 2007; accepted November 20, 2007.

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