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Keywords:

  • breast cancer;
  • breast-conserving treatment;
  • ipsilateral breast tumor recurrence;
  • distant metastases

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The clinical features of ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) for early stage breast cancer were analyzed from long-term follow-up of BCT in Japan. The purpose of this study was to clarify risk factors of IBTR and the impact of IBTR on development of distant metastases in this ethnic group.

METHODS

Patients (N = 1901)with unilateral breast cancer ≤ 3 cm in diameter who underwent BCT at 18 Japanese major breast cancer treatment institutes from 1986 to 1993 were registered in this study. Survival rates, the incidences of IBTR and distant metastases, and annual rates of IBTR and distant metastases after primary operation were calculated by the Kaplan–Meier method. A Cox proportional hazards model was used to estimate the risks of IBTR and distant metastases. A Cox model was also used to estimate the risks of distant metastases after IBTR in the group of IBTR.

RESULTS

At a median follow-up time of 107 months, the 10-year overall and disease-free survival rates were 83.9% and 77.8%, respectively. The 10-year cumulative rates of IBTR were 8.5% in the patients with postoperative irradiation and 17.2% in the patients without irradiation. The 10-year cumulative distant metastasis rate was 10.9%. On multivariate analysis, young age, positive surgical margin, and omission of radiation therapy were significant predictors of IBTR. In addition, IBTR significantly correlated with subsequent distant metastases (hazard ratio, 3.93; 95% confidence interval, 2.676–5.771; P < 0.0001). Among patients who developed IBTR, initial lymph node metastases and short interval to IBTR were significant risk factors for subsequent distant metastasis.

CONCLUSIONS

Young age, positive surgical margin, and omission of radiation therapy seemed to be important factors in relation to local control. The authors' results also indicated that IBTR is significantly associated with subsequent distant metastasis. Patients with positive nodal status at primary operation or with short interval from primary operation to IBTR are at especially high risk of distant metastasis. It remains unclear, however, whether IBTR is an indicator or a cause of subsequent distant metastases. Cancer 2006. © 2005 American Cancer Society.

Along time has passed since breast-conserving therapy (BCT) became the standard treatment modality for early stage breast cancers.1–2 The increasing number of patients treated with BCT resulted in a corresponding increase of ipsilateral breast tumor recurrence (IBTR). The main concern for both physicians and patients is, therefore, the risk of IBTR in the preserved breast.

Postoperative irradiation to the remaining breast has significantly reduced the incidence of IBTR.1–5 The results of the recent National Surgical Adjuvant Bowel and Breast Project (NSABP) B-21, showed that radiation therapy was so effective that it would even benefit early breast cancers at minimal risk for IBTR.6 Therefore, postoperative irradiation was thought to be an important part of standard procedure for BCT.

In addition to radiation therapy, some factors were reported to have an influence on IBTR. For example, young women were generally thought to have a higher frequency of local recurrence.7–11 Kroman et al. recently reported a relation between young age and increasing risk of IBTR, from a study of BCT with over 2000 patients.12 The European Organization for Research and Treatment of Cancer (EORTC) trial also confirmed the impact of age.13

The presence or absence of cancer cells at the resection margin, and their quantity, are also major factors affecting IBTR.14–19 Park et al. reported that the 8-year accrued rate of IBTR was 7% in patients with negative and close margins, 14% in those with focally positive margins, and 27% in those with extensively positive margins.14 Although the definitions of positive margin are obscure, the importance of pathologic margin status in relation to the risk of IBTR has been shown.

Many studies have shown that IBTR is associated with subsequent distant metastases (DM) and worse survival.20–28 Whether IBTR is an indicator or a cause of subsequent DM is debatable.26, 29–33 It has been proposed that IBTR is not the cause but is simply a significant indicator of subsequent DM. Other groups have recently suggested that IBTR may be a cause of DM.32, 34, 35

In the current study, we summarized the long-term follow-up results of BCT for Japanese women with breast cancer, and we focused on IBTR, particularly its incidence, risk factors, and predictive significance for subsequent DM. In Japan, BCT was adopted later than in western countries. Therefore, there are few studies summarizing the results of BCT for Japanese women.36, 37 This is the first long-term report of large-scale results of BCT in this ethnic group.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Included in this study were 1901 patients with unilateral breast cancer ≤ 3 cm in diameter who underwent BCT at 18 major institutes from 1986 to 1993. Patients who had received primary systemic therapy, and those with past history of breast cancer, were excluded. Postoperative irradiation or adjuvant therapy were not exclusion criteria. The surgical procedure consisted of wide excision or quadrantectomy plus axillary lymph node dissection.

Questionnaire forms were sent to the members of this study in November 2001 to collect clinical patient data. The questionnaire asked for data as follows: age at primary operation, menopausal status, date of primary operation, initial tumor size by palpation, histologic type, pathologic lymph node status, histologic margin status, lymphovascular invasion, nuclear grade, extensive intraductal component (EIC), estrogen receptor status (ER), progesterone receptor status (PgR), adjuvant endocrine therapy, adjuvant chemotherapy, postoperative irradiation, boost radiation, date of IBTR, method of salvage operation, systemic therapy after IBTR, secondary local recurrence and its date, distant metastases, date of distant metastases, contralateral breast cancer, death, cause of death, and date of death or last visit. Serial sections of resected specimens were meticulously examined at all institutions. Margins ≤ 5 mm from the cut edge of the specimen were usually regarded as positive margins. Measurement methods and cutoff levels of the hormone receptors were not standardized, and they varied between institutions.

IBTR was defined as all events which occurred in the remaining breast after BCT. No distinction was made between recurrence because of residual cancer cells or because of new primary cancer.

Local-free, disease-free, distant disease-free, and overall survival rates were calculated using the Kaplan–Meier method. The statistical differences of local, distant, disease-free rates, and overall survival were proved using a log-rank test for univariate analysis. Multivariate analyses for local free and distant disease-free rates were performed using the Cox proportional hazards model. In univariate and multivariate analysis, age was dealt with as a serial variable and was not categorized at a certain point, such as ≤ 35 years or older. All statistical analyses were performed with Stat View 5.0 software (SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Systemic Recurrence and IBTR

There were 1901 patients available for analysis of survival and recurrence rates. The median follow-up period was 107 months(range, 2–184 mos). Patient characteristics are shown in Table 1. There were 172 patients who developed IBTR, and 179 patients had recurrences in distant organs or regional lymph nodes. During follow-up, 182 patients died; of these, 128 patients died of their breast cancers. The 10-year overall and cause-specific survival rates were 83.9% and 92.2%, respectively. The 10-year distant disease-free survival was 77.8%. The 10-year cumulative rate of IBTR was 9.6% (8.5% in the group with postoperative irradiation and 17.2% in the group without RT). There was a significant difference between these two groups (P < 0.0001).

Table 1. Patient Characteristics
CharacteristicNo. of patients
  1. ER: estrogen receptor; PgR: progesterone receptor.

Age, yrs 
 Median49
 Range21–89
 ≤ 35135
 > 361766
Clinical tumor size, cm 
 Median17
 Range0–30
Lymph node metastasis 
 Positive380
 Negative1476
 Unknown45
ER status 
 Positive779
 Negative482
 Unknown640
PgR status 
 Positive510
 Negative430
 Unknown961
Surgical margin 
 Positive263
 Negative1503
 Uncertain135

Risk Factors for IBTR

Factors influencing IBTR are shown in Table 2. In a univariate analysis, younger age at primary operation, tumor size, positive margin status, high nuclear grade, EIC, PgR, omission of endocrine therapy, and omission of postoperative irradiation were significantly associated with IBTR. Of these, younger age, positive margin status, and omission of postoperative irradiation were independently associated with IBTR on a multivariate Cox proportional hazards model analysis.

Table 2. Factors Influencing Ipsilateral Breast Tumor Recurrence (IBTR), Results of Univariate and Multivariate Analysis
VariableUnivariate analysisMultivariate analysis
P valueHRP value95% CI
  1. HR: hazard ratio; CI: confidence interval; DCIS: ductal carcinoma in situ; IDC: invasive ductal carcinoma; Special: lobular carcinoma, medullary carcinoma, squamous cell carcinoma, etc.; ly: lymphatic invasion; v: vascular invasion; EIC: extensive intraductal component; ER: estrogen receptor; PgR: progesterone receptor.

Age< 0.00010.943< 0.00010.917–0.970
Size0.02571.0170.25570.988–1.047
Histologic type    
 DCIS/IDC/special0.6053   
Lymph node metastasis    
 +/−0.141   
Surgical margin    
 +/−< 0.00012.8490.00041.587–5.012
 ly +/−0.8768   
 v +/−0.5236   
Nuclear grade    
 3/1, 20.0650   
 EIC +/−0.01061.4220.18570.847–2.398
 ER −/+0.04930.6960.14640.427–1.135
 PgR −/+0.0036   
Chemotherapy    
 −/+0.0878   
Endocrine therapy    
 −/+0.01801.5430.08240.397–1.057
Radiation therapy    
 −/+< 0.00013.861< 0.00010.155–0.433

Time Course of IBTR and Distant Metastasis

The annual rate and cumulative incidence of IBTR after primary operation is shown in Figure 1. The peak of IBTR was seen at 3 to 4 years after primary operation, and the annual rate decreased gradually thereafter. Figure 2 shows the clinical outcome of patients with and without IBTR. Patients who developed IBTR had a significantly greater risk of developing DM (P < 0.0001).

thumbnail image

Figure 1. Annual and cumulative rates of ipsilateral breast tumor recurrence (IBTR) after primary operation are represented. The bar graph shows annual rates of IBTR. It was 1 to 2% up to 7 years from primary operation. After that, the incidences decreased slightly, but they did not reach zero. The incidence was highest at 4 to 5 years after primary operation. The line graph shows cumulative incidence of IBTR. It was linear to 7 years and a little flattened thereafter.

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thumbnail image

Figure 2. Distant-free survival after primary operation is shown according to local relapse. The distant-free survival curve shows that patients with IBTR are more likely to develop subsequent distant metastases. There was a statistically significant difference between the two groups (P < 0.0001). The actuarial distant-free survival rate at 10 years was 89.7% in the local control group and 70.3% in the IBTR group.

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Risk Factors for Distant Metastasis

Both distant disease-free and overall survival rates were significantly lower in the IBTR group. To determine whether IBTR is related to DM and patient prognosis, we verified risk factors for DM. Univariate analysis showed that initial age, lymph node metastases, margin status, lymphovascular invasion, nuclear grade, EIC, PgR, and IBTR were all significantly correlated with DM (Table 3). In a multivariate analysis, IBTR was independently associated with DM as well as with lymph node metastases. The hazard ratio (HR) associated with distant metastasis was 3.93 (95% confidence interval [CI], 2.676–5.771) in IBTR, and 3.34 (95% CI, 2.365–4.724) in node-positive patients (Table 3).

Table 3. Risk Factors for Distant Metastases After Breast Conserving Surgery, Results of Univariate and Multivariate Analysis
VariableUnivariate analysisMultivariate analysis
HRP valueHRP value95% CI
  1. HR: hazard ratio; CI: confidence interval; ly: lymphatic invasion; v: vascular invasion; EIC: extensive intraductal component; ER: estrogen receptor; PgR: progesterone receptor; IBTR: ipsilateral breast tumor recurrence.

Age0.9790.0040.99< 0.300.978–1.008
Size1.0130.10   
Lymph node metastasis     
 +/−3.55< 0.00013.34< 0.00012.365–4.724
Surgical margin     
 +/−1.460.031.300.200.873–1.926
 ly +/−2.16< 0.0001   
 v +/−1.980.002   
Nuclear grade     
 3/1, 23.320.006   
 EIC +/−0.570.03   
 ER −/+0.790.16   
 PgR −/+0.640.01   
 IBTR +/−3.72< 0.00013.93< 0.00012.676–5.771

Of 1901 patients, 172 developed IBTR, and 51 developed subsequent DM after IBTR; 27 of these patients developed distant metastases within 1 year after IBTR. Factors associated with distant metastases among patients who developed on IBTR were analyzed. Univariate analysis showed that nodal status, lymphovascular invasion, and period to IBTR were potential risk factors for DM. Initial nodal status and interval to IBTR were independent risk factors for DM by Cox proportional hazard model (Table 4). Annual rates of DM for primary operation in patients with or without IBTR were compared (Fig. 3). The incidences of DM in the group of patients with IBTR were higher than those in the group of patients without IBTR regardless of the time after operation. More interestingly, the annual rates of distant metastases in the group of patients with IBTR showed two peaks, and the incidence of DM after 9 years was remarkably high. By contrast, in the group of patients without IBTR, the incidence of DM was high at 2–4 years after primary operation and subsequently decreased.

Table 4. Risk Factors for Subsequent Distant Metastases After IBTR, Results of Univariate and Multivariate Analysis
VariableUnivariate analysisMultivariate analysis
P valueHRP value95% CI
  1. HR: hazard ratio; CI: confidence interval; ly: lymphatic invasion; v: vascular invasion; EIC: extensive intraductal component; ER: estrogen receptor; PgR: progesterone receptor; DFI: disease free interval.

Age0.1724   
Size0.5618   
Lymph node metastasis    
+/−< 0.0012.680.0081.291–5.574
Surgical margin    
+/−0.3113   
ly +/−0.01611.210.5990.888–2.506
v +/−< 0.0001   
Nuclear grade    
3/1, 2NE   
EIC +/−0.2134   
ER −/+0.4057   
PgR −/+0.2230   
DFI< 0.00010.990.0080.999–1.000
thumbnail image

Figure 3. The time distribution of distant metastases after primary operation compares the local control group (LC) and IBTR group. In the group of patients without IBTR, the incidence of DM was high at 2 to 4 years after primary operation, and it gradually decreased thereafter. By contrast, in the group of patients with IBTR, the annual rates of distant metastases showed two peaks, 4 to 5 years and 12 to 13 years after primary operation. The proportion of DM after 9 years was remarkably high.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The current study was conducted to clarify the risk factors for IBTR, as well as the impact of IBTR on distant metastases in patients with early stage breast cancer treated with BCT. We first summarized the results of BCT cases in Japan with long-term follow-up. As previously reported,36, 37 the survival rates and local control rates of BCT in Japan were favorable. Risk factors of IBTR were younger age, positive margin status, and omission of postoperative irradiation. These results were consistent with previous reports.

The 10-year cumulative rates of IBTR were 8.5% and 17.2% in patients with and without radiation therapy, respectively. On a Cox proportional hazards model, postoperative irradiation decreased the risk of IBTR by about one-fourth (HR, 0.259, 95% CI, 0.214–0.431, P < 0.0001). This result is similar to the result of Early Breast Cancer Trialists' Collaborative Group (EBCTCG) metaanalysis.38

In the current study, positive surgical margins were also associated with an increased risk of IBTR as previously reported.14–18 However, definitions of margin status are not standardized. Some researchers defined it only as “positive” or “negative”.16, 20 Other studies have assessed surgical margin according to distance from the cut edge,17 but these distances varied by < 1 mm, < 2mm, or < 10mm.14, 19, 39 In the current study, the majority of close margins (≤ 5 mm from the cut edge of the specimen) were regarded as positive margins. Although judgment of margin status depends on each institution, meticulous histologic assessment was done in all institutions. (The removed specimens are examined by expert pathologists at each institute, by using 5 mm sections.)

The influence of young age on the risk of IBTR is striking. It has been supported by many previous studies.7–11 Jobsen et al. reported that age < 40 years was the only significant predictor of IBTR for women treated with BCT with pathologic T1 tumors and negative lymph node status.10 Harrold et al. showed a correlation with young age and IBTR by using a cut-point age of 40 years.40 Freedman et al. also found age to be a risk factor of IBTR, but their cut-point age was 55 years.9 Fourquet et al. categorized patients into 4 age groups (< 32, 32–45, 46–55, > 55).7 In our series, age was analyzed as a serial variable. The results are that the younger the patient, the higher the risk of IBTR. It was noteworthy that younger age was a risk factor of IBTR regardless of age cut-point.

Our results also showed that IBTR was significantly correlated with DM, as shown by several other reports.19–24 The HR was 3.93 by multivariate analysis. This ratio was very similar to that of NSABP B-06.20 When compared with the relative risk (3.34) of lymph node metastasis for distant metastasis, IBTR has almost the same impact on DM.

One of the aims of this study was to clarify what type of IBTR is likely to develop subsequent DM. Univariate analysis showed that initial lymph node metastases, lymphovascular invasion, nuclear grade, and the interval from primary operation to IBTR were significantly associated with DM. Short DFI was reported to be highly correlated with subsequent DM.21, 25, 26, 31, 41–44 These risk factors appear to reflect the inherent aggressive characteristics of primary tumors.38, 39 Thus the risk of developing DM would be predetermined before treatment, with local recurrence being a manifestation of this risk.

The time distribution of annual rates of DM among patients with IBTR showed a noteworthy pattern. Two peaks in the incidence of DM were observed; 4 to 5 years and 12 to 13 years after primary operation. In patients without IBTR, a peak of incidence was seen 3 to 4 years after primary operation, with a gradual decrease thereafter. Our results agreed with the long-term results of NSABP B-06 and some other studies.32, 33 Some groups have presumed that the second peak of DM was due to IBTR.28, 29 Considering that late distant metastases are not likely to develop so frequently after mastectomy, IBTR may be a cause of DM in such cases. Up to now, many investigators thought that IBTR was only a marker for DM19, 20, 23, 24 because many cases of IBTR that subsequently developed DM had more aggressive primary tumor characteristics. Recently, however, it appears that additional radiation may lead to a survival benefit, suggesting IBTR may, in part, be a cause of DM, especially in cases of IBTR who develop late DM.45

Classifying IBTR into true recurrence (TR) or new primary tumor (NP) is one of the concerns. The finding that cumulative incidence of IBTR is linear to 7 years and flattens slightly thereafter (Table 1. line graph) suggests that not a few cases of late recurrence may be NP recurrence. In the current study, we did not distinguish a second primary breast cancer from true recurrence because it is difficult to correctly diagnose. Some studies suggest the prognostic significance of IBTR from this viewpoint. True recurrence is generally thought to have worse prognosis than a new primary tumor.46–48 Haffty and colleagues speculated that a certain portion of IBTR contained new primary tumor and biologic behaviors were quite different.48, 49 So it is noteworthy that IBTR represent two distinct entities, and classifying IBTR may help our understanding of the complicated behavior of IBTR.

In summary, young age, positive surgical margin, and omission of radiation therapy are independent risk factors for IBTR, and IBTR was certainly correlated with subsequent DM. Initial nodal status and the interval to IBTR were significantly associated with DM after IBTR. It remains unclear whether IBTR is an indicator of DM or a cause of it. Further study is needed to solve this question.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002; 347: 12331241.
  • 2
    Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002; 347: 12271232.
  • 3
    Clark RM, Whelan T, Levine M, et al. Randomized clinical trial of breast irradiation after lumpectomy and axillary dissection for node-negative breast cancer: an update. J Natl Cancer Inst. 1996; 88: 16591664.
  • 4
    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. Uppsala-Orebro Breast Cancer Study Group. J Natl Cancer Inst. 1994; 86: 717722.
  • 5
    Forrest AP, Stewart HJ, Everington D, et al. Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Scottish Cancer Trials Breast Group. Lancet. 1996; 348: 708713.
  • 6
    Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in woman with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002; 20: 41414149.
  • 7
    Fourquet A, Campana F, Zafrani B, et al. Prognostic factors of breast recurrence in the conservative management of early breast cancer: A 25-year follow-up. Int J Radiat Oncol Biol Phys. 1989; 17: 719725.
  • 8
    Locker AP, Ellis IO, Morgan DAL, et al. Factors influencing local recurrence after excision and radiotherapy for primary breast cancer. Br J Surg. 1989; 76: 890894.
  • 9
    Freedman GM, Hanlon AL, Fowble BL, et al. Recursive partitioning identifies patients at high and low risk for ipsilateral tumor recurrence after breast-conserving surgery and radiation. J Clin Oncol. 2002; 20: 40154021.
  • 10
    Jobsen JJ, van der Palen J, Meerwaldt JH. The impact of age on local control in women with pT1 breast cancer treated with conservative surgery and radiation therapy. Eur J Cancer. 2001; 37: 18201827.
  • 11
    Arriagada R, Le MG, Contesso G, et al. Predictive factors for local recurrence in 2006 patients with surgically resected small breast cancer. Ann Oncol. 2002; 13: 14041413.
  • 12
    Kroman N, Holtveg H, Wohlfahrt J, et al. Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with breast carcinoma. Cancer. 2004; 15: 688693.
  • 13
    Vrieling C, Collette L, Fourquet A, et al. Can patient-, treatment- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients? Eur J Cancer. 2003; 39: 932944.
  • 14
    Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol. 2000; 18: 16681675.
  • 15
    Renton SC, Gazet J-C, Ford HT, et al. The impact of the resection margin in conservative surgery for breast cancer. Eur J Surg Oncol. 1996; 22: 1722.
  • 16
    Mansfield CM, Komarnicky LT, Schwartz GF, et al. Ten-year results in 1070 patients with stages I and II breast cancer treated by conservative surgery and radiation therapy. Cancer. 1995; 75: 23282336.
  • 17
    Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg. 2002; 184: 383393.
  • 18
    Smitt MC, Nowels K, Carlson RW, et al. Predictor of reexcision findings and recurrence after breast conservation. Int J Radiot Oncol Biol Phys. 2003; 57: 979985.
  • 19
    Peterson ME, Schultz DJ, Reynolds C, et al. Outcomes in breast cancer patients relative to margin status after treatment with breast-conserving surgery and radiation therapy: the University of Pennsylvania experience. Int J Radiat Oncol Biol Phys. 1999; 15: 10291035.
  • 20
    Fisher B, Anderson S, Fisher ER, et al. Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet. 1991; 338: 327331.
  • 21
    Veronesi U, Marubini E, Del Vecchio M, et al. Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events. J Natl Cancer Inst. 1995; 87: 1927.
  • 22
    Kurtz JM, Spitalier JM, Amalric R, et al. The prognostic significance of late local recurrence after breast-conserving therapy. Int J Radiat Oncol Biol Phys. 1990; 18: 8793.
  • 23
    Whelan T, Clark R, Roberts R, et al. Ipsilateral breast tumor recurrence postlumpectomy is predictive of subsequent mortality: results from a randomized trial. Int J Radiat Oncol Biol Phys. 1994; 30: 1116.
  • 24
    Kemperman H, Borger J, Hart A, et al. Prognostic factors for survival after breast conserving therapy for stage I and II breast cancer. The role of local recurrence. Eur J Cancer. 1995; 31A: 690698.
  • 25
    Haffty BG, Reiss M, Beinfield M, et al. Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse. J Clin Oncol. 1996; 14: 5257.
  • 26
    Freedman GM, Fowble B. Local recurrence after mastectomy or breast-conserving surgery and radiation. Oncology (Huntingt). 2000; 14: 156181.
  • 27
    Fowble BL. Ipsilateral breast tumor recurrence following breast-conserving surgery for early-stage invasive cancer. Acta Oncol. 1999; 38( Suppl 13): 917.
  • 28
    Meric F, Mirza NQ, Vlastos G, et al. Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy. Cancer. 2003; 97: 926933.
  • 29
    Della Rovere GQ, Benson RJ. Ipsilateral breast tumor recurrence of breast cancer: determinant or indicator of poor prognosis. Lancet Oncol. 2002; 3: 183187.
  • 30
    Vicini FA, Kestin L, Huang R, Martinez A. Does local recurrence affect the rate of distant metastases and survival in patients with early-stage breast carcinoma treated with breast-conserving therapy? Cancer. 2003; 15: 910919.
  • 31
    McBain CA, Young EA, Swindell R, et al. Local recurrence of breast cancer following surgery and radiotherapy: incidence and outcome. Clin Oncol (R Coll Radiol). 2003; 15: 2523.
  • 32
    Fisher ER, Anderson S, Tan-Chiu E, et al. Fifteen-year prognostic discriminants for invasive breast carcinoma. National Surgical Adjuvant Breast and Bowel Project Protocol-06. Cancer. 2001; 91: 16791687.
  • 33
    Recht A, Silen W, Schnitt SJ, et al. Time-course of local recurrence following conservative surgery and radiotherapy for early stage breast cancer. Int J Radiat Oncol Biol Phys. 1988; 15: 255261.
  • 34
    Fortin A, Larochelle M, Laverdiere J, et al. Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol. 1999; 17: 101109.
  • 35
    Cowen D, Houvenaeghel G, Bardou V, et al. Local and distant failures after limited surgery with positive margins and radiotherapy for node-negative breast cancer. Int J Radiat Oncol Biol Phys. 2000; 47: 305312.
  • 36
    Kodaira T, Fuwa N, Itoh Y, et al. Aichi Cancer Center 10-year experience with conservative breast treatment of early breast cancer: retrospective analysis regarding failure patterns and factors influencing local control. Int J Radiat Oncol Biol Phys. 2001; 49: 13111316.
  • 37
    Ohsumi S, Sakamoto G, Takashima S, et al. Long-term results of breast-conserving treatment for early-stage breast cancer in Japanese women from multicenter investigation. Jpn J Clin Oncol. 2003; 33: 6167.
  • 38
    Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomized trials. Lancet. 2000; 355: 17571770.
  • 39
    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. 1999; 13: 14551461.
  • 40
    Harrold EV, Turner BC, Matloff ET, et al. Local recurrence in the conservatively treated breast cancer patients: a correlation with age and family history. Cancer J Sci Am. 1998; 4: 302307.
  • 41
    Le MG, Arriagada R, Spielmann M, et al. Prognostic factors for death after an isolated local recurrence in patients with early-stage breast carcinoma. Cancer. 2002; 94: 28132820.
  • 42
    Schmoor C, Sauerbrei W, Bastert G, et al. Role of isolated locoregional recurrence of breast cancer: results of four prospective studies. J Clin Oncol. 2000; 18: 16961708.
  • 43
    Touboul E, Buffat L, Belkacemi Y, et al. Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer. Int J Radiot Oncol Biol Phys. 1999; 43: 2538.
  • 44
    Haffty BG, Fischer D, Beinfield M, et al. Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys. 1991; 21: 293298.
  • 45
    Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst. 2004; 96: 115121.
  • 46
    Smith TE, Lee D, Turner BC, et al. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys. 2000; 48: 12811289.
  • 47
    Huang E, Buchholz TA, Meric F, et al. Classifying local disease recurrences after breast conservation therapy based on location and histology: new primary tumors have more favorable outcomes than true local disease recurrences. Cancer. 2002; 95: 20592067.
  • 48
    Haffty BG, Carter D, Flynn SD, et al. Local recurrence versus new primary: clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting. Int J Radiat Oncol Biol Phys. 1993; 27: 575583.
  • 49
    Lannin D, Haffty BG. End results of salvage therapy after failure of breast-conservation surgery. Oncology. 2004; 18: 272279.