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Brachytherapy Boost to the Tumour Bed in High Risk Patients After Limited Surgery for Breast Cancer
Clinical Oncology (2003) 15: 156–159 doi:10.1053/clon.2002.0187
Original Article Brachytherapy Boost to the Tumour Bed in High Risk Patients After Limited Surgery for Breast Cancer H. C. Ulutin, D. Ash, D. Dodwell Yorkshire Regional Centre for Clinical Oncology, Cookridge Hospital, Leeds, U.K. ABSTRACT: The results of treatment for 174 patients at high risk of local recurrence, referred for radiotherapy after conservative surgery for early breast cancer, are evaluated. Microscopic margin involvement, extensive carcinoma in situ, and vascular/lymphatic invasion were the main risk factors for local recurrence. Whole-breast irradiation (40 Gy in 15 fractions over 3 weeks) followed with a brachytherapy boost (Ir192 wire implant or PDR Ir192) of 25 Gy was applied. Median follow-up was 80 months. The actuarial 6-year overall survival rate was 91% and the within breast recurrence-free survival was 88%. The most common risk factor among those recurring within the breast was involved surgical margins (13 out of 17). Cosmesis was reported to be good or excellent in 79% of cases. In patients at high risk for local recurrence, tumour-bed boost with brachytherapy can provide satisfactory local control after limited surgery and external radiotherapy. Ulutin, H. C. et al. (2003). Clinical Oncology 15, 156–159 2003 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Brachytherapy, tumour-bed boost, breast cancer, conservative surgery Received: 15 April 2002
Revised: 23 October 2002
Introduction
The place of radiotherapy after breast-conserving surgery (BCS) and the lack of any mortality detriment after breast conservation with adjuvant radiotherapy compared with mastectomy have been confirmed by numerous studies [1]. Large tumour size, microscopic involvement of resection margins, the presence of extensive in situ carcinoma (EIC) and vascular/ lymphatic invasion within and around the primary tumour are common risk factors that are related to local recurrence [2]. Most breast recurrences after BCS are at or near the previous excision site. Increasing the boost dose of irradiation may optimize local control [3]. We report a series of patients that have risk factors for local recurrence, to evaluate a breast-conserving therapy (BCT) technique using a 25 Gy-brachytherapy boost. Materials and Methods
One hundred and seventy-four patients were treated between 1981 and 1996. The results for all patients treated by brachytherapy in this hospital during this time are included. All patients had pathologically proven carcinoma of breast treated surgically by a breast-conserving operation. Wide local excision, Author for correspondence: D. Dodwell, Yorkshire Regional Centre for Clinical Oncology, Cookridge Hospital, Leeds LS16 6QB, U.K. 0936–6555/03/030156+04 $35.00/0
Accepted: 25 October 2002
lumpectomy, and quadrantectomy with or without axillary dissection were the surgical techniques employed. The presence of margin involvement and/or other possible adverse pathological findings, such as an extensive in situ component, and vascular/lymphatic invasion were necessary for patient inclusion. An involved surgical margin was defined as tumour seen immediately at the inked edge of the resection margin. Margins were not considered to be close or positive when involved solely by in situ carcinoma. The intraductal component was considered extensive (EIC+) if the number of ducts with intraductal cancer in breast tissue directly adjacent to the primary tumour was 10 or more. Tumours consisting predominantly of carcinoma in situ with focal areas of invasion were also classified as EIC+. Vascular invasion was considered to be present if distinct tumour emboli were seen in more than three endothelium-lined vessels (blood/lymphatic). Information on cosmesis was derived retrospectively from hospital records according to the physicians’ assessment of cosmesis. Systemic Therapy
Sixteen patients received no systemic therapy, 74 patients received Tamoxifen, 18 patients received chemotherapy and 66 received both chemotherapy and Tamoxifen. Cyclophosphamide 100 mg/m2, orally days 1 to 14, methotrexate 35 mg/m2 i.v. days 1 and 8 and
2003 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
5-fluorouracil (5-FU) 600 mg/m2 days 1 and 8 repeated every 28 days for six cycles (CMF: 70 patients) or 5-FU 600 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 i.v. for six cycles repeated every 21 days (FEC: 14 patients) were the chemotherapy regimens employed.
157
Table 1 – Distribution of patients by pathological stage (%)
pN0 pN1 pNx
pT1
pT2
pT3
48 (28) 18 (10) 54 (31)
14 (8) 17 (10) 15 (9)
2 (1) 0 (0) 6 (3)
Radiotherapy
Standard radiotherapy after BCS at this centre [4] includes a dose of 40 Gy in 15 fractions over 3 weeks (2.67 Gy/fraction) to the whole breast using two (tangential) wedged opposing 6 MV photon fields. The dose was prescribed at a point in the midplane of the breast corresponding to the ICRU point [5]. The minimum and the maximum dose in the central plane were greater than 95% and less than 110% of the prescribed dose. A boost was given either with an Ir192 wire volume implant (in 139 patients) or with Ir192 sourced pulse dose rate micro-selectron (in 35 patients) to the tumour bed. A brachytherapy boost was initiated at a mean of 16 days (range 5–38 days) after external beam therapy, by applying plastic templates and rigid steel needles to construct a two-plane implant. The target volume included the original tumour volume with margins of approximately 2 cm. The separation of the needles was usually 1.8 or 2 cm and the implant was loaded such that the ends of the active iridium wire lay 0.5 cm below the skin surface. Up to 12 sources per implant were used but the majority contained seven sources with four in the deep plane and three in the superficial plane of most two plane implants. The average length of the sources used was 6.25 cm (range 2.8–11 cm). A dose of 25 Gy was prescribed to the 85% (reference) isodose according to the Paris dosimetry system [6] and the mean insertion time was 69 h. For pulse dose rate insertions mean insertion time was 49 h. Follow-up and Statistics
The patients were followed at 4-month intervals for the first 2 years, 6-month intervals for the next 3 years, and thereafter annually. Overall and breast recurrence-free survival rates, calculated from the date of surgery, were estimated according to the Kaplan–Meier method [7]. Cox proportional hazards model was used to evaluate the effect of factors on local failure. The small number of local failures (n=17) limited our ability to perform multivariate analysis. Results Patient Characteristics
The mean age of the patients was 48.5 years (range 25–75 years). Patient details by pathological stage are given in Table 1 and by histological type in Table 2.
Table 2 – Distribution of patients by histological type and grade, (%)
Invasive ductal Invasive lobular Invasive carcinoma NOS
G1
G2
G3
Gx
23 (13) 8 (5) 0 (0)
30 (17) 22 (13) 0 (0)
52 (30) 10 (6) 0 (0)
4 (2) 5 (3) 20 (11)
Pathology
Microscopic involvement of resection margins with invasive breast cancer was present in 102 patients. Extensive in situ carcinoma (ductal in 26 cases, lobular in 12 cases) within and adjacent to the invasive tumour was positive in 38 patients. Extensive vascular and/or lymphatic invasion was observed in 34 patients (Table 3).
Outcome
Median follow-up was 80 months (15 to 120 months). Thirteen patients developed a within-breast recurrence while four patients developed a within-breast recurrence plus distant metastatic disease. Seventeen patients developed distant metastases without local recurrence. Three patients had an axillary recurrence alone and two had axillary recurrence plus distant metastatic disease. Of 17 breast recurrences 13 (76%) were in the previously excised quadrant, while remaining four (24%) were peripheral. The mean age for salvage mastectomy for recurrence was 42.2 years (range 31–45). All breast recurrences were successfully salvaged by mastectomy. Ten patients have died of breast cancer. The actuarial 6-year survival is 91.1% and the within-breast recurrence-free survival 87.7% (Fig. 1). The mean time to within-breast recurrence was 37 months (range 8–72 months). For those patients remaining free of local recurrence, clinicians’ assessment of cosmesis was reported as ‘good or excellent’ in 137 patients and ‘fair’ in 18 patients. Two patients were judged to have a poor cosmetic result. There was no obvious difference in cosmesis between wire implant or PDR. Pathological details of the patients who recurred within the breast are presented in Table 4. The commonest risk factor among those recurring within the breast was involved surgical margins (13 out of 17) but this represents only 13% of the total with this risk factor
158
Table 3 – Distribution of pathological risk factors according to age in 174 patients Only margin involvement
Only EIC†
Only V/LI‡
Margin involvement+EIC
Margin involvement+V/LI
n=42* n=50
n=20 n=18
n=18 n=16
n=2 n=1
n=4 n=3
Age c45 Age >45
*n: Number of patients. †EIC: Extensive in situ carcinoma. ‡V/LI: Vascular/lymphatic involvement.
Fig. 1. – Actuarial overall survival (bold line) and breast recurrence-free survival.
[87% (89/102) of women with involved surgical margins remained free of local recurrence]. In univariate analysis, the only significant factor which effected local control was involved margin status (P=0.038, 95% CI: 0.844–0.997). Young age (as a factor increasing the local recurrence risk) was close to significance (P=0.059, 95% CI: 0.989–1.001). Discussion
Randomized trials have reported local tumour recurrence rates of approximately 10% at 5 years after BCT
for early-stage disease [8]. Margin status at the resection site is one of the strongest prognostic factors for local control [9–11]. In 733 women with pathological stage I and II disease, the adverse influence of positive margins on local control was demonstrated [12]. Voogd et al. [13] investigated the risk factors of 360 women with local recurrence after BCT, and reported significant increase in risk of local recurrence with microscopic margin involvement. In a further study of 885 patients with clinical stage I–II disease, it was shown that a positive margin was a risk factor for local and distant recurrence. BCT with radiation boost to the primary site for margin positive, EIC-negative tumours was suggested [14]. Another factor that affects local control is vascular invasion [15–17]. In our series 34 patients were treated with an implant for this reason, and so far the results appear satisfactory with only two local recurrences. In some studies EIC is a predictive factor [18,19]. Holland et al. [20] in an analysis of a series of mastectomy specimens showed that the incidence of residual disease was 74% for tumours with EIC vs. 42% without EIC. Lindley et al. [17] also found that high-grade intraductal carcinoma was associated with a high risk of local recurrence. In more recent series EIC is no longer considered to be a predictive factor of local recurrence
Table 4 – Details of patients who recurred within the breast by pathological stage, grade, histological type, and main risk factor
Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Stage
Grade
Histological
Risk factor
pT2pNx pT2pNx pT2pNx pT2pNx pT1pNx pT2pNx pT1pNx pT2pNx pT2pNx pT2pNx pT1pN1 pT2pNx pT3pN0 pT2pNx pT2pNx pT2pNx pT1pNx
3 2 3 2 X 3 2 2 3 3 3 3 3 2 2 3 2
Ductal Ductal Ductal Lobular NOS Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal
Involved margins Involved margins Involved margins Extensive LCIS Involved margins Involved margins Involved margins Extensive DCIS Involved margins Involved margins Involved margins Vascular/lymphatic invasion Involved margins Involved margins Vascular/lymphatic invasion Involved margins Involved margins
when the margins after initial surgery or re-excision are negative [21–23]. Furthermore, in the presence of EIC, more extensive conservative surgery such as quadrantectomy seems to reduce the risk of local recurrence [24]. In our own series only one patient out of 26 with extensive ductal carcinoma in situ and one out of 12 with extensive lobular carcinoma in situ had local recurrences. In many studies, young age has also often been found to increase the risk of local recurrence [25–28]. Recht et al. [2] demonstrated a 5-year local recurrence rate of 26% for patients under 35 compared with 10% for older patients. The relatively young mean age of the patients in our study (48.5 years) and the mean age of those recurring in the breast (42.2 years) are consistent with this. In conclusion, consideration should always be given to further surgery if there is margin involvement [1], but patient refusal or other factors may compromise this ideal. The results of this study suggest that if microscopic tumour is found at resection margins, or there are other risk factors, recurrence rates can still be kept acceptably low with the use of a high-dose brachytherapy tumour-bed boost. References 1 Guidance on Cancer Services. Improving outcomes in breast cancer (2002) – The Research Evidence for the Manual Update. www.nice.org.uk 2 Recht A, Connolly JL, Schnitt SJ, Silver B, Rose MA, Love SM. The effect of young age on tumour recurrence in the treated breast after conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 1988;14:3–10. 3 Wazer DE, Ullrich RK, Ruthazer R, et al. Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 1998;40:851–858. 4 Rathmell AJ, Ash DV. Radiotherapy after conservative surgery: selective use of iridium-192 wire boost to tumour bed in high risk patients. Clin Oncol 1991;3:204–208. 5 ICRU. Dose specification for reporting external beam therapy with photons and electrons. Washington, DC. ICRU publications 1987: ICRU Report no: 29. 6 Pierquin B, Dutreix A, Paine CH, Marinello G, Ash D. The Paris system in interstitial radiation therapy. Acta Radiol Oncol 1978;17:33–48. 7 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 8 Early Breast Cancer Trialists’ Colloborative Group. N Engl J Med 1995;333:1462–1465. 9 Di Biase SJ, Komarnicky LT, Schwartz GF, Xie Y, Mansfield CM. The number of positive margins influences the outcome of women treated with breast preservation for early stage breast carcinoma. Cancer 1998;82:2212–2220. 10 Smitt MC, Nowels K, Jeffery S, Carlson RC, Stockdale EF, Goffinet DR. The importance of lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995;76:259–267.
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11 Heimann R, Powers C, Halpern HJ, Michel AG. Breast preservation in stage I and II carcinoma of the breast: the University of Chicago experience. Cancer 1996;78:1722–1730. 12 Di Biase SJ, Komornicky LT, Heron DE, Schvartz GF, Mansfield CM. Influence of radiation dose on positive surgical margins in women undergoing breast conservation therapy. Int J Radiat Oncol Biol Phys 2002;53:680–686. 13 Voogd AC, Peterse JL, Crommelin MA, et al. Histological determinants for different types of local recurrence after BCT of invasive breast cancer. Dutch Study Group on local recurrence after breast conservation (BORST). Eur J Cancer 1999;35: 1752–1754. 14 Schnitt SJ, Abner A, Gelman R, et al. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast conserving surgery and radiation therapy. Cancer 1994;74:1746–1751. 15 Veronesi U, Marubini E, Del Veicchio M, et al. Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst 1995;87:19–27. 16 Borger J, Kemperman H, Hart A, Peterse H, Van Dongen J, Bartelink H. Risk factors in breast-conservation therapy. J Clin Oncol 1994;12:653–660. 17 Lindley R, Burman A, Parsons P, Philips R, Henry K, Ellis H. Histologic features predictive of an increase risk of early recurrence after treatment of breast cancer by local tumour excision and radical radiotherapy. Surgery 1989;105:13–20. 18 Bartelink H, Borger JH, Van Dogen JA, Peterse JL. The impact of tumour size and histology on local control after breast-conserving therapy. Radiother Oncol 1988;11:297–303. 19 Vicini FA, Recht A, Abner A, et al. Recurrence in the breast following conservative surgery and radiation therapy for early stage breast cancer. J Natl Cancer Inst 1992;11:33–39. 20 Holland R, Veling SHJ, Mravunac M, Hendriks JHCL. Histologic multifocality of Tis, T-1–2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56: 979–990. 21 Fourquet A, Campana F, Zafrani B, et al. Prognostic factors in the conservative management for early breast cancer: a 25-year follow-up at the Institut Curie. Int J Radiat Oncol Biol Phys 1989;17:719–725. 22 Gage I, Schnit SJ, Nixon AJ, et al. Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy. Cancer 1996;78:1921–1928. 23 Schnitt SJ, Abner A, Gelman R, et al. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast-conserving surgery and radiation therapy. Cancer 1994;74:1746–1751. 24 Veronesi U, Volterrani F, Luini A, et al. Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 1990;6: 671–673. 25 De La Rochefordie´re A, Asselain B, Campana F, et al. Age as a prognostic factor in premenopausal breast carcinoma. Lancet 1993;341:1039–1043. 26 Dewar JA, Arriagada R, Benhhamou S, et al. for the IGR Cancer Group. Local relapse and contralateral tumour rates in patients with breast cancer treated with conservative surgery and radiotherapy (Institut Gustave Roussy 1970–1982). Cancer 1995;76:2260–2265. 27 Fowble BL, Schultz DJ, Overmoyer B, et al. The influence of young age on outcome in early stage breast cancer. Int J Radiat Oncol Biol Phys 1994;30:23–33. 28 Kurtz JM, Jacquemier J, Amlaric R, et al. Risk factors for breast recurrence in premenopausal patients with ductal cancers treated by conservation therapy. Cancer 1990;65:1867–1878.
Original Article Brachytherapy Boost to the Tumour Bed in High Risk Patients After Limited Surgery for Breast Cancer H. C. Ulutin, D. Ash, D. Dodwell Yorkshire Regional Centre for Clinical Oncology, Cookridge Hospital, Leeds, U.K. ABSTRACT: The results of treatment for 174 patients at high risk of local recurrence, referred for radiotherapy after conservative surgery for early breast cancer, are evaluated. Microscopic margin involvement, extensive carcinoma in situ, and vascular/lymphatic invasion were the main risk factors for local recurrence. Whole-breast irradiation (40 Gy in 15 fractions over 3 weeks) followed with a brachytherapy boost (Ir192 wire implant or PDR Ir192) of 25 Gy was applied. Median follow-up was 80 months. The actuarial 6-year overall survival rate was 91% and the within breast recurrence-free survival was 88%. The most common risk factor among those recurring within the breast was involved surgical margins (13 out of 17). Cosmesis was reported to be good or excellent in 79% of cases. In patients at high risk for local recurrence, tumour-bed boost with brachytherapy can provide satisfactory local control after limited surgery and external radiotherapy. Ulutin, H. C. et al. (2003). Clinical Oncology 15, 156–159 2003 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Brachytherapy, tumour-bed boost, breast cancer, conservative surgery Received: 15 April 2002
Revised: 23 October 2002
Introduction
The place of radiotherapy after breast-conserving surgery (BCS) and the lack of any mortality detriment after breast conservation with adjuvant radiotherapy compared with mastectomy have been confirmed by numerous studies [1]. Large tumour size, microscopic involvement of resection margins, the presence of extensive in situ carcinoma (EIC) and vascular/ lymphatic invasion within and around the primary tumour are common risk factors that are related to local recurrence [2]. Most breast recurrences after BCS are at or near the previous excision site. Increasing the boost dose of irradiation may optimize local control [3]. We report a series of patients that have risk factors for local recurrence, to evaluate a breast-conserving therapy (BCT) technique using a 25 Gy-brachytherapy boost. Materials and Methods
One hundred and seventy-four patients were treated between 1981 and 1996. The results for all patients treated by brachytherapy in this hospital during this time are included. All patients had pathologically proven carcinoma of breast treated surgically by a breast-conserving operation. Wide local excision, Author for correspondence: D. Dodwell, Yorkshire Regional Centre for Clinical Oncology, Cookridge Hospital, Leeds LS16 6QB, U.K. 0936–6555/03/030156+04 $35.00/0
Accepted: 25 October 2002
lumpectomy, and quadrantectomy with or without axillary dissection were the surgical techniques employed. The presence of margin involvement and/or other possible adverse pathological findings, such as an extensive in situ component, and vascular/lymphatic invasion were necessary for patient inclusion. An involved surgical margin was defined as tumour seen immediately at the inked edge of the resection margin. Margins were not considered to be close or positive when involved solely by in situ carcinoma. The intraductal component was considered extensive (EIC+) if the number of ducts with intraductal cancer in breast tissue directly adjacent to the primary tumour was 10 or more. Tumours consisting predominantly of carcinoma in situ with focal areas of invasion were also classified as EIC+. Vascular invasion was considered to be present if distinct tumour emboli were seen in more than three endothelium-lined vessels (blood/lymphatic). Information on cosmesis was derived retrospectively from hospital records according to the physicians’ assessment of cosmesis. Systemic Therapy
Sixteen patients received no systemic therapy, 74 patients received Tamoxifen, 18 patients received chemotherapy and 66 received both chemotherapy and Tamoxifen. Cyclophosphamide 100 mg/m2, orally days 1 to 14, methotrexate 35 mg/m2 i.v. days 1 and 8 and
2003 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
5-fluorouracil (5-FU) 600 mg/m2 days 1 and 8 repeated every 28 days for six cycles (CMF: 70 patients) or 5-FU 600 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 i.v. for six cycles repeated every 21 days (FEC: 14 patients) were the chemotherapy regimens employed.
157
Table 1 – Distribution of patients by pathological stage (%)
pN0 pN1 pNx
pT1
pT2
pT3
48 (28) 18 (10) 54 (31)
14 (8) 17 (10) 15 (9)
2 (1) 0 (0) 6 (3)
Radiotherapy
Standard radiotherapy after BCS at this centre [4] includes a dose of 40 Gy in 15 fractions over 3 weeks (2.67 Gy/fraction) to the whole breast using two (tangential) wedged opposing 6 MV photon fields. The dose was prescribed at a point in the midplane of the breast corresponding to the ICRU point [5]. The minimum and the maximum dose in the central plane were greater than 95% and less than 110% of the prescribed dose. A boost was given either with an Ir192 wire volume implant (in 139 patients) or with Ir192 sourced pulse dose rate micro-selectron (in 35 patients) to the tumour bed. A brachytherapy boost was initiated at a mean of 16 days (range 5–38 days) after external beam therapy, by applying plastic templates and rigid steel needles to construct a two-plane implant. The target volume included the original tumour volume with margins of approximately 2 cm. The separation of the needles was usually 1.8 or 2 cm and the implant was loaded such that the ends of the active iridium wire lay 0.5 cm below the skin surface. Up to 12 sources per implant were used but the majority contained seven sources with four in the deep plane and three in the superficial plane of most two plane implants. The average length of the sources used was 6.25 cm (range 2.8–11 cm). A dose of 25 Gy was prescribed to the 85% (reference) isodose according to the Paris dosimetry system [6] and the mean insertion time was 69 h. For pulse dose rate insertions mean insertion time was 49 h. Follow-up and Statistics
The patients were followed at 4-month intervals for the first 2 years, 6-month intervals for the next 3 years, and thereafter annually. Overall and breast recurrence-free survival rates, calculated from the date of surgery, were estimated according to the Kaplan–Meier method [7]. Cox proportional hazards model was used to evaluate the effect of factors on local failure. The small number of local failures (n=17) limited our ability to perform multivariate analysis. Results Patient Characteristics
The mean age of the patients was 48.5 years (range 25–75 years). Patient details by pathological stage are given in Table 1 and by histological type in Table 2.
Table 2 – Distribution of patients by histological type and grade, (%)
Invasive ductal Invasive lobular Invasive carcinoma NOS
G1
G2
G3
Gx
23 (13) 8 (5) 0 (0)
30 (17) 22 (13) 0 (0)
52 (30) 10 (6) 0 (0)
4 (2) 5 (3) 20 (11)
Pathology
Microscopic involvement of resection margins with invasive breast cancer was present in 102 patients. Extensive in situ carcinoma (ductal in 26 cases, lobular in 12 cases) within and adjacent to the invasive tumour was positive in 38 patients. Extensive vascular and/or lymphatic invasion was observed in 34 patients (Table 3).
Outcome
Median follow-up was 80 months (15 to 120 months). Thirteen patients developed a within-breast recurrence while four patients developed a within-breast recurrence plus distant metastatic disease. Seventeen patients developed distant metastases without local recurrence. Three patients had an axillary recurrence alone and two had axillary recurrence plus distant metastatic disease. Of 17 breast recurrences 13 (76%) were in the previously excised quadrant, while remaining four (24%) were peripheral. The mean age for salvage mastectomy for recurrence was 42.2 years (range 31–45). All breast recurrences were successfully salvaged by mastectomy. Ten patients have died of breast cancer. The actuarial 6-year survival is 91.1% and the within-breast recurrence-free survival 87.7% (Fig. 1). The mean time to within-breast recurrence was 37 months (range 8–72 months). For those patients remaining free of local recurrence, clinicians’ assessment of cosmesis was reported as ‘good or excellent’ in 137 patients and ‘fair’ in 18 patients. Two patients were judged to have a poor cosmetic result. There was no obvious difference in cosmesis between wire implant or PDR. Pathological details of the patients who recurred within the breast are presented in Table 4. The commonest risk factor among those recurring within the breast was involved surgical margins (13 out of 17) but this represents only 13% of the total with this risk factor
158
Table 3 – Distribution of pathological risk factors according to age in 174 patients Only margin involvement
Only EIC†
Only V/LI‡
Margin involvement+EIC
Margin involvement+V/LI
n=42* n=50
n=20 n=18
n=18 n=16
n=2 n=1
n=4 n=3
Age c45 Age >45
*n: Number of patients. †EIC: Extensive in situ carcinoma. ‡V/LI: Vascular/lymphatic involvement.
Fig. 1. – Actuarial overall survival (bold line) and breast recurrence-free survival.
[87% (89/102) of women with involved surgical margins remained free of local recurrence]. In univariate analysis, the only significant factor which effected local control was involved margin status (P=0.038, 95% CI: 0.844–0.997). Young age (as a factor increasing the local recurrence risk) was close to significance (P=0.059, 95% CI: 0.989–1.001). Discussion
Randomized trials have reported local tumour recurrence rates of approximately 10% at 5 years after BCT
for early-stage disease [8]. Margin status at the resection site is one of the strongest prognostic factors for local control [9–11]. In 733 women with pathological stage I and II disease, the adverse influence of positive margins on local control was demonstrated [12]. Voogd et al. [13] investigated the risk factors of 360 women with local recurrence after BCT, and reported significant increase in risk of local recurrence with microscopic margin involvement. In a further study of 885 patients with clinical stage I–II disease, it was shown that a positive margin was a risk factor for local and distant recurrence. BCT with radiation boost to the primary site for margin positive, EIC-negative tumours was suggested [14]. Another factor that affects local control is vascular invasion [15–17]. In our series 34 patients were treated with an implant for this reason, and so far the results appear satisfactory with only two local recurrences. In some studies EIC is a predictive factor [18,19]. Holland et al. [20] in an analysis of a series of mastectomy specimens showed that the incidence of residual disease was 74% for tumours with EIC vs. 42% without EIC. Lindley et al. [17] also found that high-grade intraductal carcinoma was associated with a high risk of local recurrence. In more recent series EIC is no longer considered to be a predictive factor of local recurrence
Table 4 – Details of patients who recurred within the breast by pathological stage, grade, histological type, and main risk factor
Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Stage
Grade
Histological
Risk factor
pT2pNx pT2pNx pT2pNx pT2pNx pT1pNx pT2pNx pT1pNx pT2pNx pT2pNx pT2pNx pT1pN1 pT2pNx pT3pN0 pT2pNx pT2pNx pT2pNx pT1pNx
3 2 3 2 X 3 2 2 3 3 3 3 3 2 2 3 2
Ductal Ductal Ductal Lobular NOS Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal Ductal
Involved margins Involved margins Involved margins Extensive LCIS Involved margins Involved margins Involved margins Extensive DCIS Involved margins Involved margins Involved margins Vascular/lymphatic invasion Involved margins Involved margins Vascular/lymphatic invasion Involved margins Involved margins
when the margins after initial surgery or re-excision are negative [21–23]. Furthermore, in the presence of EIC, more extensive conservative surgery such as quadrantectomy seems to reduce the risk of local recurrence [24]. In our own series only one patient out of 26 with extensive ductal carcinoma in situ and one out of 12 with extensive lobular carcinoma in situ had local recurrences. In many studies, young age has also often been found to increase the risk of local recurrence [25–28]. Recht et al. [2] demonstrated a 5-year local recurrence rate of 26% for patients under 35 compared with 10% for older patients. The relatively young mean age of the patients in our study (48.5 years) and the mean age of those recurring in the breast (42.2 years) are consistent with this. In conclusion, consideration should always be given to further surgery if there is margin involvement [1], but patient refusal or other factors may compromise this ideal. The results of this study suggest that if microscopic tumour is found at resection margins, or there are other risk factors, recurrence rates can still be kept acceptably low with the use of a high-dose brachytherapy tumour-bed boost. References 1 Guidance on Cancer Services. Improving outcomes in breast cancer (2002) – The Research Evidence for the Manual Update. www.nice.org.uk 2 Recht A, Connolly JL, Schnitt SJ, Silver B, Rose MA, Love SM. The effect of young age on tumour recurrence in the treated breast after conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 1988;14:3–10. 3 Wazer DE, Ullrich RK, Ruthazer R, et al. Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 1998;40:851–858. 4 Rathmell AJ, Ash DV. Radiotherapy after conservative surgery: selective use of iridium-192 wire boost to tumour bed in high risk patients. Clin Oncol 1991;3:204–208. 5 ICRU. Dose specification for reporting external beam therapy with photons and electrons. Washington, DC. ICRU publications 1987: ICRU Report no: 29. 6 Pierquin B, Dutreix A, Paine CH, Marinello G, Ash D. The Paris system in interstitial radiation therapy. Acta Radiol Oncol 1978;17:33–48. 7 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 8 Early Breast Cancer Trialists’ Colloborative Group. N Engl J Med 1995;333:1462–1465. 9 Di Biase SJ, Komarnicky LT, Schwartz GF, Xie Y, Mansfield CM. The number of positive margins influences the outcome of women treated with breast preservation for early stage breast carcinoma. Cancer 1998;82:2212–2220. 10 Smitt MC, Nowels K, Jeffery S, Carlson RC, Stockdale EF, Goffinet DR. The importance of lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995;76:259–267.
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11 Heimann R, Powers C, Halpern HJ, Michel AG. Breast preservation in stage I and II carcinoma of the breast: the University of Chicago experience. Cancer 1996;78:1722–1730. 12 Di Biase SJ, Komornicky LT, Heron DE, Schvartz GF, Mansfield CM. Influence of radiation dose on positive surgical margins in women undergoing breast conservation therapy. Int J Radiat Oncol Biol Phys 2002;53:680–686. 13 Voogd AC, Peterse JL, Crommelin MA, et al. Histological determinants for different types of local recurrence after BCT of invasive breast cancer. Dutch Study Group on local recurrence after breast conservation (BORST). Eur J Cancer 1999;35: 1752–1754. 14 Schnitt SJ, Abner A, Gelman R, et al. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast conserving surgery and radiation therapy. Cancer 1994;74:1746–1751. 15 Veronesi U, Marubini E, Del Veicchio M, et al. Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst 1995;87:19–27. 16 Borger J, Kemperman H, Hart A, Peterse H, Van Dongen J, Bartelink H. Risk factors in breast-conservation therapy. J Clin Oncol 1994;12:653–660. 17 Lindley R, Burman A, Parsons P, Philips R, Henry K, Ellis H. Histologic features predictive of an increase risk of early recurrence after treatment of breast cancer by local tumour excision and radical radiotherapy. Surgery 1989;105:13–20. 18 Bartelink H, Borger JH, Van Dogen JA, Peterse JL. The impact of tumour size and histology on local control after breast-conserving therapy. Radiother Oncol 1988;11:297–303. 19 Vicini FA, Recht A, Abner A, et al. Recurrence in the breast following conservative surgery and radiation therapy for early stage breast cancer. J Natl Cancer Inst 1992;11:33–39. 20 Holland R, Veling SHJ, Mravunac M, Hendriks JHCL. Histologic multifocality of Tis, T-1–2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56: 979–990. 21 Fourquet A, Campana F, Zafrani B, et al. Prognostic factors in the conservative management for early breast cancer: a 25-year follow-up at the Institut Curie. Int J Radiat Oncol Biol Phys 1989;17:719–725. 22 Gage I, Schnit SJ, Nixon AJ, et al. Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy. Cancer 1996;78:1921–1928. 23 Schnitt SJ, Abner A, Gelman R, et al. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast-conserving surgery and radiation therapy. Cancer 1994;74:1746–1751. 24 Veronesi U, Volterrani F, Luini A, et al. Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 1990;6: 671–673. 25 De La Rochefordie´re A, Asselain B, Campana F, et al. Age as a prognostic factor in premenopausal breast carcinoma. Lancet 1993;341:1039–1043. 26 Dewar JA, Arriagada R, Benhhamou S, et al. for the IGR Cancer Group. Local relapse and contralateral tumour rates in patients with breast cancer treated with conservative surgery and radiotherapy (Institut Gustave Roussy 1970–1982). Cancer 1995;76:2260–2265. 27 Fowble BL, Schultz DJ, Overmoyer B, et al. The influence of young age on outcome in early stage breast cancer. Int J Radiat Oncol Biol Phys 1994;30:23–33. 28 Kurtz JM, Jacquemier J, Amlaric R, et al. Risk factors for breast recurrence in premenopausal patients with ductal cancers treated by conservation therapy. Cancer 1990;65:1867–1878.