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10-Year Results After Sector Resection With or Without Postoperative Radiotherapy for Stage I Breast Cancer: A Randomized Trial

From the Department of Surgery, Örebro Medical Center Hospital, Örebro; Departments of Surgery, Oncology, and Pathology, University Hospital, Uppsala; Departments of Pathology and Mammography, Falu Hospital, Falun; Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; and the Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, MA.

Address reprint requests to Göran Liljegren, MD, PhD, Department of Surgery, Örebro Medical Center Hospital, S-701 85 Örebro, Sweden; email goran.liljegren{at}orebroll.se

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To study the long-term effectiveness of postoperative radiotherapy after sector resection for breast cancer in a randomized trial in which mammography is a major pathway to diagnosis.

PATIENTS AND METHODS: Three hundred eighty-one women with a unifocal breast cancer 20 mm in diameter on the preoperative mammogram and without histopathologic signs of axillary metastases were treated by sector resection plus axillary dissection. Of these patients, 184 women were randomized to receive postoperative radiotherapy to the breast (XRT group), and 197 women received no further treatment (non-XRT group).

RESULTS: The local recurrence rate was 8.5% (95% confidence interval [CI], 3.9% to 13.1%) in the XRT group and 24.0% (95% CI, 17.6% to 30.4%) in the non-XRT group (P = .0001). Survival free from regional and distant recurrence was 83.3% in the XRT group (95% CI, 77.5% to 89.1%) and 80.0% in the non-XRT group (95% CI, 73.9% to 86.1%) (P = .23). Overall survival was 77.5% in the XRT group (95% CI, 70.9% to 84.1%) and 78% in the non-XRT group (95% CI, 71.7% to 84.3%) (P = .99). A subgroup analysis suggested that women older than 55 years of age without comedo or lobular carcinomas had a low risk of local recurrence of 6.1% (95% CI, 0.1% to 9.1%) in the XRT-group and 11.0% (4.0% to 18.0%) in the non-XRT group (P = .16).

CONCLUSION: Sector resection plus radiotherapy resulted in an absolute reduction in local recurrence of 16% at 10 years compared with surgery alone. Women older than 55 years of age without comedo or lobular carcinomas may have a low risk of local recurrence. Postoperative radiotherapy was not shown to reduce distant recurrences or improve overall survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE LONG-TERM effectiveness of routine postoperative radiotherapy after breast-conserving treatment of breast cancer has not previously been assessed in clinical trials carried out in the era of mammography screening or in patients treated surgically by a standardized sector resection.

We report 10-year results of a clinical trial in which patients with stage I¹ breast cancer were randomized to postoperative radiotherapy or follow-up only after sector resection with a strictly standardized technique and meticulous confirmation of complete excision.² We also update an analysis of risk factors for local recurrence³ that attempted to define a subgroup of women who are at low risk for local relapse, even without postoperative radiotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Design
The study design has previously been described in detail.⁴ Women younger than 80 years with a unifocal, mammographically visible breast cancer and with a maximal tumor diameter of 20 mm or less on the preoperative mammogram were eligible. All patients were subjected to a standardized sector resection, as previously described.⁵ Nonpalpable lesions were localized by the wire-hook technique⁶ or by the stereotactic application of dye (coal or methylene blue).⁷ To ensure complete tumor excision, the protocol stipulated perioperative x-ray of the specimen. The axilla was dissected to levels I and II.⁸ No adjuvant systemic therapy was given. Patients were eligible for randomization provided that the specimen was histopathologically free from multifocal in situ lesions and from invasive lesions outside 20 mm from the border of the primary tumor. The axillary nodes were required to be histopathologically free from metastases. Patients were ineligible if the tumor was transected during surgery. Full informed consent was required. The study was approved by the ethical committees with jurisdiction for the participating centers.

Randomization
After stratification for participating center, mode of detection (screening or clinical diagnosis), and tumor size ( 10 mm or 11 to 20 mm), the patients were randomized to receive either postoperative radiotherapy (XRT group) or surgery alone (non-XRT group). Allocation to treatment group was performed in blocks of four within each center and stratum.

Radiotherapy
The radiotherapy technique has previously been described in detail.⁴ In short, the breast parenchyma plus 1 cm was defined as the target volume. Two opposing tangential fields with an open angle of 185 degrees were applied. Radiotherapy was delivered by photons from a 4-to-10–MV linear accelerator or a cobalt-60 unit. A total dose of 54 Gy in 27 fractions was given at the rate of five fractions per week. No boost was applied to the tumor bed.

Patient Accrual
Patient accrual started in October 1981. Five central county hospitals and one university hospital enrolled patients for the study. Patient accrual terminated in September 1988, at which time 389 patients had been included. However, eight were excluded because of ineligibility; thus the trial included 381 patients. Eleven women who did not accept postoperative irradiation were analyzed according to the assigned treatment group, as were four women who never began this treatment due to complications (postoperative infection, two patients; cerebrovascular incident, one patient; and suicide, one patient).

Patient Selection
We reviewed the records for all patients with invasive breast cancer in histopathologic stage I diagnosed in the defined catchment area of the participating centers from October 1981 through October 1986. The inclusion criteria were fulfilled by approximately 50% of all stage I breast cancers. Major reasons for ineligibility were multiple tumors (36%) or undefinable tumor size on mammography (31%). Seventy-four percent of all eligible patients in the defined source population were entered onto the trial. There was no evidence of selection by age and tumor characteristics.

Evaluation Procedures
The follow-up procedures consisted of (1) a minimum of two visits per year with a physician participating in the study, (2) mammography performed annually or more often if indicated by clinical findings, and (3) a chest x-ray performed 1 year after diagnosis. Further investigations were undertaken only when clinical signs indicated distant metastases. From 5 years postoperatively, a yearly visit with a physician participating in the study or the patient's general practitioner was performed, which included mammography. The closing date of follow-up for this analysis was April 30, 1997. The median follow-up time was 109 months in the XRT group and 103 months in the non-XRT group, with a total of 3,037 person-years in the study. Table 1 shows the distribution of selected clinical variables in the two treatment groups. A local recurrence in the breast was defined as any cytologically or histopathologically confirmed invasive or in situ carcinoma in the ipsilateral breast. Local recurrences were classified as (1) recurrence in the surgical field, (2) new primary cancers in quadrants outside the surgical field, (3) metastases in an intramammary lymph node, or (4) recurrence in the cuticular tissue. Recurrence in the ipsilateral axilla was classified as a regional recurrence.

Estimates of disease-free survival took into account all types of regional and distant metastases (including regional recurrences in the axilla). Every patient contributed person-years to the date of the type of recurrence analyzed, regardless of whether another type of event preceded it; eg, if a local recurrence developed first, the patient was still eligible for analysis of distant metastases after the local recurrence. In two patients, death from disseminated disease was the first sign of relapse.

In the analysis of risk factors for local recurrence, all histopathologic slides were reevaluated by the study pathologist (A.L.). To validate the histopathologic classification of tumor type, the slides from one of the participating centers (n = 71) were reevaluated by a second pathologist (H.N.). The preoperative mammograms and the perioperative specimen x-rays were reevaluated by the study mammographer (L.T.). Both pathologists and the mammographer were blinded to the patient outcome. All patient records were reviewed for identification of patient characteristics, tumor characteristics, and events during the primary treatment.

Definition of Evaluation Variables
Patient characteristics. Age (at the day of operation) was analyzed as a continuous variable. Women were considered premenopausal if their last menstruation was 3 months ago, perimenopausal if their last menstruation was more than 3 months but less than 5 years ago, and postmenopausal if their last menstruation was 5 years ago. Mode of tumor detection was classified as either detected via screening or detected due to the presence of symptoms. Patient characteristics are listed in Table 2.

Histopathologic tumor characteristics (Table 2). Tumors containing intraductal carcinoma both inside and outside the index tumor were classified as positive for extensive intraductal component (EIC+). All other tumors were considered to be EIC-negative (EIC-). Tumors with estrogen receptor and progesterone receptor levels 0.1 fmol/ng DNA were defined as receptor-positive. Tumor size was analyzed as a continuous variable according to maximum histopathologic size. The histopathologic type was categorized according to the World Health Organization classification⁹ and supplemented by a further subdivision into three groups of the invasive ductal carcinomas according to the classification system suggested by Linell et al.¹⁰ Ductal carcinomas were thus subdivided into tubuloductal, comedo (poorly differentiated ductal), and ductal (not otherwise specified [NOS]) types as earlier described.³ The tubuloductal and ductal (NOS) type were grouped together. Tumor grade was analyzed according to the Bloom-Richardson classification system.¹¹ Nuclear grade was classified as low, medium, or high. Vascular invasion was defined according to the presence of invasion into the blood and/or lymphatic vessels or the absence of such invasion. Resection margins were classified as less than or greater than 5 mm in the lateral dimension on the histopathologic examination. Medical records were used to determine whether or not the tumor was palpable at diagnosis.

Mammographic tumor characteristics. The mammographic appearance on the preoperative mammogram was classified into five groups according to the appearance of the density (stellate or circular/oval), the presence of microcalcifications (inside or outside the density), and the presence of more than one tumor. In addition, parenchymal pattern on the preoperative mammogram was classified into five groups¹² according to an evolution of Wolfe's patterns.¹³ We separated Wolfe's pattern DY into two groups, patterns 1 and 5. Our pattern 1 may be compared to Wolfe's QDY pattern, our pattern 2 is identical to Wolfe's N1 pattern, and our pattern 3 is identical to Wolfe's P1. Our pattern 4 matches Wolfe's P2 pattern, and pattern 5 corresponds to Wolfe's DY pattern. Pattern 1 may change into pattern 2 (ie, entirely fatty) or pattern 3 (ie, retroareolar linear pattern due to periductal elastosis) during a woman's lifetime. Mammographic tumor characteristics are listed in Table 3.

Statistical Analyses
On the basis of previously reported results,^14,15 we assumed a priori that approximately 5% of the XRT group would develop a local tumor recurrence after 5 years. We wanted to be able to detect a local recurrence rate in the non-XRT group that would be 15% or higher at a 5% level of significance (two-sided test) and 90% power. With these considerations, the predetermined sample size was 360 patients. The probabilities of disease-free survival and overall survival were estimated with the life-table method. The differences between the curves were tested with the log-rank test.¹⁶ Risk factors for local recurrence were analyzed in univariate and multivariate Cox proportional hazards models.¹⁷ Age (years) and tumor diameter (mm) were kept as continuous variables, whereas other variables were categorized and represented as dummy variables in the analysis. In the multivariate analyses, tumor size, tumor grade, vessel invasion, and histopathologic type were introduced stepwise to analyze their influence on the estimate for age. In all steps, radiotherapy and operation year were included and adjusted for in the multiple logistic regression by keeping these two characteristics in all models. Nonirradiated patients were the reference group. The estimates obtained in the models are given as relative hazards (RH) with 95% confidence intervals (CI). P = .05 was considered to be the level of statistical significance.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Local Recurrences
During the follow-up period, a local recurrence developed in 57 patients, 13 of whom had been randomized to the XRT group. Of these 13 women, one received no radiotherapy due to postoperative infection, whereas two other women refused radiotherapy. A fourth woman developed a local relapse during radiotherapy, at which time her therapy was discontinued.

After 10 years, the local recurrence rate was 8.5% (95% CI, 3.9% to 13.1%) in the XRT group and 24.0% (95% CI, 17.6% to 30.4%) in the non-XRT group (Fig 1). The life-table curves were statistically significantly different (P = .0001). The estimated difference between the recurrence rates in the two groups at 10 years was 15.5% (95% CI, 13.7 to 17.3%). This difference implies that the number of patients who must be treated with postoperative radiotherapy to prevent one local recurrence (number needed to treat) is six. Thirty-eight (67%) of all local recurrences occurred in the surgical field. Two were in the cuticular scar, and two were in the skin overlying the surgical field. Thirteen tumor recurrences developed in the breast parenchyma outside the field of surgery, and one was in an intramammary lymph node. Five recurring tumors were multifocal; in one instance, the tumor was a lymphangiosarcoma in an irradiated breast. Three of the recurrences were in situ carcinomas.

View larger version (15K): [in this window] [in a new window]   Fig 1. Probability of being free from local recurrence. Numbers at bottom indicate patients at risk.

In the XRT group, 10 of 13 women with local recurrences were treated with mastectomy. In the non-XRT group, 14 women with a local recurrence were treated with a second breast-conserving procedure, and postoperative radiotherapy was given to nine of these women. The remaining 30 women underwent mastectomy. Systemic treatment was administered to five women with a local recurrence in each treatment group. Two of the women from the XRT group received CMF combination chemotherapy (ie, intravenous cyclophosphamide 600 mg/m², methotrexate 40 mg/m², and fluorouracil 600 mg/m²) in nine courses at 3-weekly intervals; the others were treated with tamoxifen (20 mg/d) for a minimum of 2 years.

Regional and/or Distant Recurrence
In 28 patients assigned to the XRT group and in 36 assigned to the non-XRT group, regional and/or distant metastatic disease was the first sign of relapse. The difference between the groups is entirely explained by eight more axillary recurrences in the non-XRT group. Seven women in the XRT group and five women in the non-XRT group had both regional and distant recurrences. After 10 years, the estimated survival free from regional and distant recurrences was 83.3% (95% CI, 77.5% to 89.1%) in the XRT group and 80.0% (95% CI, 73.9% to 86.1%) in the non-XRT group (Fig 2). The probabilities of remaining free from regional and distant disease did not differ in a statistically significant way between the treatment groups (P = .29).

View larger version (15K): [in this window] [in a new window]   Fig 2. Probability of being free from regional and/or distant metastases. Numbers at bottom indicate patients at risk.

Contralateral Breast Cancer
A contralateral breast cancer occurred in 28 patients (17 in the XRT group and 11 in the non-XRT group). At 10 years, the incidence of contralateral cancer was 10.5% (95% CI, 5.4% to 15.6%) in the XRT group and 6.5% (95% CI, 2.7% to 10.3%) in the non-XRT group. The life-table curves did not differ significantly (P = .19) (data not shown).

Survival
During the study period, a total of 86 patients died, 41 (47%) with breast cancer as the underlying cause of death (22 in the XRT group and 19 in the non-XRT group). Cardiovascular disease as the cause of death was observed among 11 women in the XRT group and 20 women in the non-XRT group. At 10 years, the life-table estimates of overall survival were 77.5% (95% CI, 70.9% to 84.1%) for women in the XRT group and 78.0% (95% CI, 71.7% to 84.3%) for women in the non-XRT group (Fig 3). The life-table curves were almost identical (P = .99).

View larger version (15K): [in this window] [in a new window]   Fig 3. Probability of being alive (overall survival). Numbers at bottom indicate patients at risk.

Risk Factors for Local Recurrence
Patient characteristics: univariate analysis (Table 2). Risk for local recurrence decreased by 3% (95% CI, 1% to 6%) per year of increasing age, which corresponds with a reduction of almost 50% during 20 years of increasing age. The only other estimate of RH that also was statistically significant was if the patient was postmenopausal (RH = 0.48; 95% CI, 0.28 to 0.81).

Histopathologic tumor characteristics: univariate analysis (Table 2). Presence of a comedo type cancer was associated with a statistically increased risk for local recurrence compared with tubuloductal and ductal cancers (RH = 3.60; 95% CI, 2.0 to 6.4). The lobular type was also associated with a higher risk of local recurrence than that of the tubuloductal and ductal type (RH = 3.2; 95% CI, 1.4 to 7.1) Besides histopathologic type, lymphatic/vascular invasion compared with no lymphatic/vascular invasion (RH = 1.9; 95% CI, 1.1 to 3.5) and high tumor grade compared with intermediate and low tumor grade (RH = 2.5; 95% CI, 1.4 to 4.7) were the only other histopathologic statistically significant risk factors for a local recurrence. Validation of the histopathology by the second pathologist (H.N.) resulted in the same histopathologic type in 89% of the cases.

Mammographic characteristics: univariate analysis (Table 3). Risk of local recurrence was higher if the tumor on the mammogram appeared as a circular/oval-shaped density compared with a stellate lesion (RH = 2.5; 95% CI, 1.4 to 4.5). Mammographic appearance of a stellate lesion with microcalcifications inside the lesion and microcalcifications outside the lesion were also associated with a higher risk of local recurrence compared with the appearance of a stellate lesion, but with wider confidence intervals. Mammographic parenchymal patterns (modified Wolfe's pattern), mammographic signs of multifocality, or margin less than 10 mm on the specimen x-ray were not identified as risk factors of local recurrence.

Multivariate analysis. A multivariate Cox proportional hazards survival analysis of the risk factors that reached or approached statistical significance in the univariate analysis was also performed (Table 4). In the analysis, adjustment was made for treatment group and operation year. First age was analyzed, followed by stepwise introduction of tumor size, tumor grade, vessel invasion, and histopathologic type. Age was identified as a statistically significant risk factor with a 3% risk reduction per year of increasing age in all five models. High tumor grade elevated the risk by approximately 2.5 times in two of the three models in which it was used, but it was not a statistically significant risk factor when histopathologic type was also included in the multivariate model. When histopathologic type was introduced, the comedo type elevated the risk by 2.2 times and the lobular type by 2.5 times compared with tubuloductal and ductal type. Tumor size and vessel invasion were not significant risk factors for local recurrence in the multivariate analysis, nor were any of the mammographic risk factors that were statistically significant or that approached statistical significance in the univariate analysis (data not shown).

Identification of a low-risk population. Based on the risk factor analysis, we carried out a life-table analysis in a subgroup of women who were older than 55 years of age and without comedo or lobular carcinomas (46% of the study population; Fig 4). Among these women, the 10-year local recurrence rate was 6.1% (95% CI, 0.1% to 12.1%) in the XRT group and 11.0% (95% CI, 4.0% to 18.0%) in the non-XRT group. These two life-table curves were not statistically significantly different (P = .16). The difference between the groups implies that 20 women must be treated with postoperative radiotherapy to prevent one local recurrence in this subgroup of patients (number needed to treat = 20).

View larger version (15K): [in this window] [in a new window]   Fig 4. Probability of being free from local recurrence, low-risk group (> 55 years of age without comedo or lobular carcinoma). Numbers at bottom indicate patients at risk.

For the present analysis, several manual checks revealed that eight patients with medial located tumors, seven of whom were in the XRT group, received radiotherapy to parasternal lymph nodes. A reanalysis with those patient excluded did not change the presented results.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Since this trial started in 1981, five other randomized clinical trials have evaluated the role of routine postoperative radiotherapy after breast-conserving surgery.^18-23 All of them, including a meta-analysis,²⁴ show that postoperative radiotherapy to the remaining breast improves local tumor control but has no evident impact on survival. Our study is the only of these trials that explores the efficacy of routine postoperative radiotherapy in patients with stage I breast cancer and mammography as the main route to diagnosis.

Our trial was designed to show whether a meticulous surgical technique can replace postoperative adjuvant radiotherapy to obtain local tumor control after breast-conserving surgery. The results from this study compared with the primary aim demonstrate that radiotherapy still should be standard therapy. However, we found a lower local recurrence rate in both treatment arms than in trials using lumpectomy rather than sector resection.^19-23 Thus the surgical technique may influence local control independent of radiotherapy.^2,18,20,23 Differences in the local recurrence rates between trials may also reflect patient selection. A substantial proportion (45%) of the participants in our study had their cancers detected at mammography screening. Hence, our results are likely to be applicable in a setting in which there is a mammography screening program in operation.

Contrary to Clark et al,²² we identified a tentative subgroup with a low risk of local recurrence at 10 years. The prospective studies from the Milan Cancer Institute^18,20 as well as several retrospective studies^25-29 have identified low age as a risk factor. Because our study design stipulated the same meticulous surgical control of radicality for all patients, our findings contradict the idea that increase in risk with lower age is due to confounding by wider indications for breast conservation and lesser resections in younger patients. We speculate that higher levels of estrogen—and to some extent, progesterone—stimulate growth factors (insulin-like growth factor 1, insulin-like growth factor 2, epidermal growth factor, and transforming growth factor alpha) in stroma and epithelial cells.³⁰ Also, the comedo and lobular type of tumors have been associated with higher risk for local relapse, but only in retrospective studies.^31-36 The results from analyses on the association between mammographic characteristics and risk for recurrence have been conflicting,^37-39 and our own results point only toward weak associations that tend to disappear after correction for histopathologic findings.

Our results indicate that in a subgroup of patients, the cost-effectiveness of routine use of radiotherapy to the breast after a sector resection is low,⁴⁰ because recurrence rate without irradiation is only approximately 1% per year. Our ad hoc–developed criteria are straightforward and can be independently tested in other clinical trials with ease. Any decision not to irradiate must be made after careful consideration of the clinical characteristics, surgical treatment, nature of the disease, and patient preferences. Older age cannot be used as the only criterion; the operative procedure must be locally radical, and the disease should be unifocal and stage I.

Clearly, our results do not apply to patients with more advanced disease and do not address the effectiveness of radiotherapy given to regional lymph nodes, demonstrating survival gains by the addition of postoperative radiotherapy.^24,41,42 In the patient domain evaluated in this clinical trial and in which mammography is a main route to diagnosis, the absolute gain by routine addition of postoperative radiotherapy is a reduction of local recurrences by approximately 16% at 10 years. Our trial was not designed to explore survival differences and cannot rule out a small advantage in survival by the addition of postoperative radiotherapy after sector resection.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Protocol committee: H.O. Adami, S. Graffman, L. Holmberg.

Principal investigators: L. Holmberg, H.O. Adami, G. Liljegren.

Study coordinators: G. Liljegren, L. Holmberg.

Preparation of manuscript: G. Liljegren, L. Holmberg, J. Bergh, A. Lindgren, L. Tabár, H. Nordgren, H.O. Adami.

Participating investigators: Central Hospital, Falun: A. Cohen, U. Ljungqvist; Department of Surgery, A. Lindgren, Department of Pathology, L. Tabár, Department of Mammography. Central Hospital, Västerås: L. Bergkvist, Department of Surgery; L. Johansson, Department of Oncology. University Hospital, Uppsala: L. Holmberg, Department of Surgery, J. Bergh, T. Jansson, Department of Oncology, H. Nordgren, Department of Pathology. Central Hospital, Eskilstuna: Å. Rimsten, Department of Surgery; B. Stenstam, Department of Oncology. Central Hospital, Karlstad: T. Jahnberg, Department of Surgery; M. Söderberg, Department of Oncology. Örebro Medical Center Hospital: G. Liljegren, Department of Surgery; G. Westman, Department of Oncology. Karolinska Institute, Stockholm: H.O. Adami, Department of Medical Epidemiology.

Consulting statistician: B. Huitfeldt.

	ACKNOWLEDGMENTS

 
This study was supported by grants from the Swedish Cancer Society (project no. 1266-B94-15XEE) and from the Örebro County Medical Research Fund (project no. 200136).

We thank A. Jennische, Department of Surgery, University Hospital, Uppsala, Sweden, for devoted and high-quality secretarial assistance.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. International Union Against Cancer: TNM Classification of Malignant Tumors. Geneva, Switzerland, International Union Against Cancer, 1974

2. Liljegren G, Holmberg L, Adami HO, et al: Sector resection with or without postoperative radiotherapy for stage I breast cancer: Five-year results of a randomized trial. J Natl Cancer Inst86:717-722, 1994[Abstract/Free Full Text]

3. Liljegren G, Lindgren A, Bergh J, et al: Risk factors for local recurrence after conservative treatment in stage I breast cancer: Definition of a subgroup not requiring radiotherapy. Ann Oncol8:235-241, 1997[Abstract/Free Full Text]

4. Uppsala-Örebro Breast Cancer Study Group: Sector resection with or without postoperative radiotherapy for stage I breast cancer: A randomized trial. J Natl Cancer Inst82:277-282, 1990[Abstract/Free Full Text]

5. Aspegren K, Holmberg L, Adami HO: Standardisation of the surgical technique in breast conserving treatment of mammary cancer. Br J Surg75:807-810, 1988[Medline]

6. Frank HA, Hall FM, Steer ML: Preoperative localization of nonpalpable breast lesions demonstrated by mammography. N Engl J Med295:259-260, 1976[Medline]

7. Raininko R, Linna MI, Räsänen O: Preoperative localization of nonpalpable breast tumors. Duodecim142:574-578, 1976

8. Siegel BM, Mayzel KA, Love SM: Level I and II axillary dissection in the treatment of early-stage breast cancer. Arch Surg125:1144-1147, 1990[Abstract/Free Full Text]

9. World Health Organization: Histological Typing of Breast Tumors (ed 2). Geneva, Switzerland, World Health Organization, 1981

10. Linell F, Ljungberg O, Andersson I: Breast carcinomas: Aspects of early stages, progression and related problems. Acta Pathol Microbiol Scand Suppl 1-233, 1980 (suppl 272)

11. Bloom HJB, Richardson WW: Histological grading and prognosis in breast cancer: A study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer11:35-77, 1957

12. Gram I, Funkhouser E, Tabár L: The Tabár classification of mammographic parenchymal patterns. Eur J Radiol24:131-136, 1997[Medline]

13. Wolfe JN: Breast patterns as index of risk for developing breast cancer. Am J Roentgenol126:1130-1139, 1976[Abstract]

14. Veronesi U, Saccozzi R, Del Vecchio M, et al: Comparing radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. N Engl J Med305:6-11, 1981[Abstract]

15. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med320:822-828, 1989[Abstract]

16. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer35:1-39, 1977[Medline]

17. Cox OR: Regression model and life tables. J R Stat Soc34:187-220, 1972

18. Veronesi U, Luini A, Del Vecchio M, et al: Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med328:1587-1591, 1993[Abstract/Free Full Text]

19. Fisher B, Andersson S, Redmond C, et al: Reanalysis after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med333:1456-1461, 1995[Abstract/Free Full Text]

20. Veronesi U, Salvadori B, Luini A, et al: Breast conservation is a safe method in patients with small cancer of the breast: Long-term results of three randomized trials on 1,973 patients. Eur J Cancer 31A:1574-1579, 1995

21. Forrest AP, Stewart HJ, Everington D, et al: Randomized controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Lancet348:708-713, 1996[Medline]

22. Clark M, Whelan T, Levine M, et al: Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: An update. J Natl Cancer Inst88:1659-1664, 1996[Abstract/Free Full Text]

23. Renton SC, Gazet JC, Ford HT, et al: The importance of resection margin in conservative surgery for breast cancer. Eur J Surg Oncol22:17-22, 1996[Medline]

24. Early Breast Cancer Trialists Collaborative Group: Effects of radiotherapy and surgery in early breast cancer. N Engl J Med333:1444-1455, 1995[Abstract/Free Full Text]

25. Fourquet A, Campana F, Zafrani B, et al: Prognostic factors of breast recurrence in conservative management of early breast cancer: A 25-year follow-up. Int J Radiat Oncol Biol Phys17:719-725, 1989[Medline]

26. Locker AP, Ellis IO, Morgan DAL, et al: Factors influencing local recurrence after excision and radiotherapy for primary breast cancer. Br J Surg76:890-894, 1989[Medline]

27. Kurtz JM, Spitalier J-M, Amalric R, et al: Mammary recurrences in women younger than forty. Int J Radiat Oncol Biol Phys15:271-276, 1988[Medline]

28. Mathewes RH, McNeese MO, Montague ED, et al: Prognostic implications of age in breast cancer patients treated with tumorectomy and irradiation or with mastectomy. Int J Radiat Oncol Biol Phys14:659-663, 1988[Medline]

29. de la Rochefordiere A, Asselain B, Campana F, et al: Age as a prognostic factor in premenopausal breast carcinoma. Lancet341:1039-1043, 1993[Medline]

30. Reid SE, Murphy MS, Kaufman M, et al: Endocrine and paracrine hormones in the promotion, progression and recurrence of breast cancer. Br J Surg83:1037-1046, 1996[Medline]

31. Lindley R, Bullman A, Parsons P, et al: Histologic features predictive of an increased risk of early local recurrence after treatment of breast cancer by local tumor excision and radical radiotherapy. Surgery105:13-20, 1989[Medline]

32. Kurtz JM, Jaquemier J Amalric R, et al: Risk factors for breast recurrence in premenopausal and postmenopausal patients with ductal cancer treated by conservation therapy. Cancer65:1867-1878, 1990[Medline]

33. Mate TP, Carter D, Fisher B, et al: A clinical and histopathological analysis of the results of conservation surgery and radiotherapy in stage I and II breast carcinoma. Cancer58:1995-2002, 1986[Medline]

34. Kurtz JM, Jaquemier J, Torhorst J, et al: Conservation therapy for breast cancer other than infiltrating ductal carcinomas. Cancer63:1630-1635, 1989[Medline]

35. Schnitt SJ, Connolly JL, Recht A, et al: Influence of infiltrating lobular histology on local control in breast cancer patients treated with conservative surgery and radiotherapy. Cancer64:448-454, 1989[Medline]

36. Yeatman TJ, Cantor AB, Mith TJ, et al: Tumor biology of infiltrating lobular carcinoma: Implications for management. Ann Surg222:549-561, 1995[Medline]

37. Mac Millan RO, Prushotharn AD, Codiner C, et al: Predicting local recurrence by correlating preoperative mammographic findings with pathological risk factors in patients with breast cancer. Br J Radiol68:445-449, 1995[Abstract/Free Full Text]

38. Beron PJ, Horwitz EM, Martinez AA: Pathologic and mammographic findings predicting the adequacy of tumor excision before breast-conserving therapy. AJR Am J Roentgenol167:1409-1414, 1996[Abstract/Free Full Text]

39. Dalberg K, Azavedo E, Svane G, et al: Mammographic features, predictors of early ipsilateral breast tumor recurrences? Eur J Surg Oncol22:483-490, 1996[Medline]

40. Liljegren G, Karlsson G, Bergh J, et al: The cost-effectiveness of routine postoperative radiotherapy after sector resection and axillary dissection for breast cancer stage I: Results from a randomized trial. Ann Oncol8:757-763, 1997[Abstract/Free Full Text]

41. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med337:948-955, 1997

42. Ragaz J, Jackson SM, Nuh L, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med337:956-962, 1997[Abstract/Free Full Text]

Submitted October 26, 1998; accepted April 14, 1999.

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