- Email: [email protected]
When can a second conservative approach be considered for ipsilateral breast tumour recurrence?
original article
Annals of Oncology 18: 468–472, 2007 doi:10.1093/annonc/mdl424 Published online 8 December 2006
When can a second conservative approach be considered for ipsilateral breast tumour recurrence? O. Gentilini1*, E. Botteri2, N. Rotmensz2, B. Santillo2, N. Peradze1, R. C. Saihum1, M. Intra1, A. Luini1, V. Galimberti1, A. Goldhirsch3 & U. Veronesi4 1 Division of Breast Surgery, 2Division of Epidemiology and Biostatistics, 3Department of Medical Oncology, 4Scientific Director, European Institute of Oncology, Milan, Italy
Received 30 June 2006; revised 16 October 2006; accepted 17 October 2006
(IBTR) after breast-conserving surgery (BCS).
original article
Patients and methods: One hundred and sixty-one patients with invasive IBTR who underwent a second conservative approach were retrospectively evaluated in order to describe prognosis, determine predictive factors of outcome and select the subset of patients with the best local control. Results: Fifty-seven patients (35.4%) relapsed after IBTR. Thirty-four patients (21.1%) had further in-breast recurrences and four patients (2.5%) had skin relapses. Five years cumulative incidence of local relapse was 31.4%. Twenty-four patients (17.8%, 5 years cumulative incidence) died during the follow-up. At the multivariate analysis, recurrent tumour size >2 cm was found to affect local-disease-free survival [hazard ratio (HR): 2.8, 95% confidence interval (CI) 1.2–6.2], whereas Ki-67 ‡20% and time to relapse £48 months were associated with disease-free survival (HR: 1.7, 95% CI 1.0–3.1, and HR: 2.1, 95% CI 1.2–3.6, respectively). Absence of oestrogen receptors affected overall survival (HR: 2.5, 95% CI 1.1–6.0). Among 64 patients with recurrent tumour £2 cm and time to IBTR >48 months, eight (12.8%, 5 years cumulative incidence) had further local relapses. Conclusions: Some patients with IBTR might receive a second BCS, especially when a good local control can be estimated (small recurrent tumour, late relapse), also taking into account patients’ preference. Key words: breast-conserving surgery, breast tumour, ipsilateral breast tumour recurrence
background Breast conservation is considered the treatment of first choice for early breast cancer worldwide, with a similar long-term outcome to mastectomy [1, 2]. Nevertheless, a minority of patients treated conservatively will develop ipsilateral breast tumour reappearance (IBTR) [1]. This event may in some way be considered by both physicians and patients to represent a failure of the conservative approach. In addition, relapse provokes serious anxiety in the patient, and so far, the vast majority of such women have undergone mastectomy, thus frustrating the objective of conservative surgery. Many women, however, are diagnosed with small and early-detected IBTR, which from a technical point of view might be managed with a new conservative procedure. The aim of this study was to retrospectively evaluate prognosis for patients with IBTR after breast conservation who were treated by second conservative surgery, to determine whether any predictive factors of outcome could be identified, *Correspondence to: Dr O. Gentilini, Division of Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489376; Fax: +39-02-57489780; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
and to select the subset of patients who are the best candidates for a second conservative approach.
patients and methods From April 1997 to December 2004, 12 357 patients were operated on and prospectively entered into the database of the European Institute of Oncology in Milan. Two hundred and eighty-eight consecutive patients with invasive operable IBTR as a first event and no evidence of synchronous metastatic disease were identified. For the treatment of primary cancer, all patients underwent breast-conserving surgery (BCS) followed by conventional external radiotherapy over the breast and locoregional radiotherapy whenever appropriate. Ninety-nine were operated on in our institute for the primary cancer, whereas 189 were initially operated on at a different hospital and then referred to our institute for the treatment of IBTR. At occurrence of IBTR, all patients underwent physical examination, complete staging [bone scan, chest X-ray, liver ultrasound (US) or computed tomography (CT) scan], mammography and breast US to rule out multicentricity. Magnetic resonance (MR) of the breast was carried out only in a few selected patients. One hundred and twenty-seven of 288 patients received mastectomy (44.1%), whereas 161 patients (55.9%) after a thorough discussion with the
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 12, 2015
Background: Mastectomy is considered the treatment of choice in patients with ipsilateral breast tumour recurrence
original article
Annals of Oncology
operating surgeon, underwent a further conservative approach (wide local excision with microscopic clear margins) and represent the population of the study. After the surgical treatment of IBTR, all the patients were discussed within the multidisciplinary meeting attended by surgeons, medical oncologists, radiation oncologists and pathologists and received adjuvant treatment according to staging and biological features. None of the patients received further radiation therapy after the treatment of IBTR. Median age of patients at the occurrence of IBTR was 53 years (range 24– 95). Median time to relapse was 46 months (range 4–284). Median followup was 44 months (range 4–107). One patient died from another primary tumour (pancreatic cancer) 4 months after surgery for IBTR, representing the shortest period of observation. Patients were usually followed up by physical examination every 6 months and mammography with or without breast US every year. In cases with symptoms or when clinically indicated, bone scan, chest X-ray, liver US or CT scan were carried out.
Primary end points were local-disease-free survival, disease-free survival (DFS) and overall survival (OS). Local-disease-free survival was calculated from the first IBTR to any local recurrence (i.e. second IBTR or skin recurrence). DFS was calculated from the date of first IBTR to any relapse, second primary cancer, contralateral breast cancer recurrence or death, whichever occurred first. OS was defined as the time interval from first IBTR to death from any cause. The OS and local-disease-free survival were plotted using the Kaplan– Meier method. The log-rank test was used to assess survival differences between groups in the univariate analysis. Multivariate Cox proportional hazards regression models were used to identify the prognostic independent clinico-pathological features associated with survival. All analyses were carried out with the SAS software (SAS Institute, Cary, NC). All tests were two-sided.
results Table 1 represents patients’ characteristics at presentation of primary breast cancer and at the occurrence of IBTR. In regards to further local relapses, 34 patients (21.1%) experienced a further in-breast recurrence and four patients (2.5%) had a skin relapse. Five years cumulative incidence of local relapse was 31.4%. Considering other types of events, 15 patients (9.3%) developed distant metastases, one patient (0.6%) had both local and distant metastases, one patient had a contralateral breast tumour, one patient had metastases in regional nodes and one patient experienced another primary tumour. Twenty-four patients (14.9%) died during the follow-up, with an OS at 5 years of 82.2% (Figure 1). At the univariate analysis (Table 2), recurrent tumour size >2 cm was found to be associated with poor local-disease-free survival (P value 0.002), whereas time to IBTR £48 months and absence of oestrogen receptors (ER) were close to reaching statistical significance (P value 0.062 both). For the DFS, time to relapse was the most important factor (P value 0.003), with recurrent tumour size, hormonal receptor status and Ki-67 also reaching statistical significance. Absence of ER was the most important variable affecting OS (P value 0.001) along with absence of progesterone receptors (P value 0.03) and Ki-67 ‡20 (P value 0.02). At the multivariate analysis (Table 3), recurrent tumour size >2 cm was found to independently affect local-disease-free
Volume 18 | No. 3 | March 2007
Presentation at primary cancer Age (years)
Size of tumour (cm) Regional lymph nodes involved
Histotype
Presentation at first IBTR Age (years)
Time to IBTR (months)
Size of tumour (cm)
Histotype
Oestrogen receptors Progesteron receptors Her2/neu Ki-67 Vascular invasion Multifocality
Classification
No. (%)a
<35 35–50 51–60 >60 £2 >2 0 1–3 4–9 10+ Ductal Lobular Other
19 80 34 28 107 41 88 34 11 5 129 19 11
(11.7) (49.7) (21.1) (17.4) (72.3) (27.7) (63.8) (24.6) (8.0) (3.6) (81.2) (11.9) (6.9)
<35 35–50 51–60 >60 £24 25–48 >48 £0.5 0.6–1.0 1.1–1.5 1.6–2.0 >2.0 Ductal Lobular Other Present Present Overexpressed <20% Present Present
7 61 51 42 36 55 70 16 45 54 20 16 128 13 20 125 101 19 64 26 16
(4.3) (37.9) (31.7) (26.1) (22.4) (34.2) (43.5) (10.6) (29.8) (35.8) (13.2) (10.6) (79.5) (8.1) (12.4) (78.1) (63.5) (12.2) (41.6) (17.6) (10.5)
a
Information missing for a few patients. IBTR, ipsilateral breast tumour recurrence.
Figure 1. Overall survival.
doi:10.1093/annonc/mdl424 | 469
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statistical methods
Table 1. Patients’ characteristics
original article
Annals of Oncology
survival [HR: 2.8, 95% confidence interval (CI) 1.2–6.2], whereas Ki-67 ‡20% and time to relapse <48 months were found to be associated with DFS (HR: 1.7, 95% CI 1.0–3.1, and HR: 2.1, 95% CI 1.2–3.6, respectively). Absence of ER affected OS (HR: 2.5, 95% CI 1.1–6.0). In Table 4, local-disease-free survival stratified by tumour size and time to relapse is shown. Among the 64 patients with IBTR <2 cm and time to relapse >48 months, eight (12.8%, 5 years cumulative incidence) had a further local relapse with a significantly better local-disease-free survival (P value 0.003). Figure 2 represents local-disease-free survival after the second conservative surgery.
conclusions
Table 2. Univariate analysis: clinico-pathologic features of ipsilateral breast tumour recurrence associated with survival Classification
All patients Age (years) £50 >50 Size of tumour (cm) £2 >2 Time to IBTR (months) £48 >48 Histotype Ductal Lobular Oestrogen receptors Present Absent Progesteron receptors Present Absent Her2/neu Not overexpressed Overexpressed Ki-67 (%) <20 ‡20 Vascular invasion Present Absent Multifocality Present Absent
Local-disease-free survivala Events (% 5 years P valuec cumulative incidence)
Disease-free survivalb Events (% 5 years cumulative incidence)
161
38 (31.4)
66 (50.8)
68 93
20 (39.8) 18 (24.7)
0.198
32 (55.9) 34 (47.2)
0.316
14 (25.8) 10 (12.2)
0.150
135 16
25 (22.4) 9 (71.2)
0.002
50 (46.3) 11 (75.6)
0.048
19 (17.9) 4 (26.6)
0.370
87 74
26 (41.6) 12 (18.0)
0.062
47 (61.6) 19 (34.7)
0.003
18 (22.5) 6 (11.5)
0.068
128 13
29 (30.6) 3 (27.1)
0.793
53 (52.0) 6 (50.6)
0.405
22 (20.4) 1 (14.3)
0.485
125 35
25 (26.2) 12 (48.8)
0.062
44 (43.6) 21 (72.3)
0.016
11 (13.2) 12 (34.1)
0.001
101 58
24 (31.9) 13 (27.9)
0.854
37 (45.9) 28 (58.9)
0.107
10 (14.2) 13 (25.6)
0.038
134 19
28 (28.5) 4 (26.4)
0.643
49 (46.4) 10 (57.9)
0.086
16 (15.7) 4 (30.4)
0.183
64 90
11 (18.0) 25 (40.9)
0.082
18 (33.6) 44 (61.4)
0.012
4 (11.5) 18 (22.8)
0.020
26 121
7 (36.3) 25 (26.9)
0.368
13 (57.3) 47 (49.1)
0.280
5 (24.3) 18 (17.8)
0.674
16 136
4 (44.3) 31 (30.1)
0.518
9 (67.5) 53 (48.7)
0.071
3 (20.5) 20 (18.0)
0.503
No. at risk
P valuec
Overall survival Events (% 5 years cumulative incidence)
P valuec
24 (17.8)
a
Events: ipsilateral breast tumour or skin recurrence. Events: second relapses or death without second relapses. c Differences in survival between strata are tested using the log-rank test. IBTR, ipsilateral breast tumour recurrence. b
470 | Gentilini et al.
Volume 18 | No. 3 | March 2007
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 12, 2015
So far, IBTR after breast conservation has been dogmatically treated by mastectomy, even in patients with small recurrences which might have been managed conservatively. We believe that
the occurrence of IBTR should not be considered per se a failure of the conservative approach and that in some patients there exists the possibility to successfully repeat breast conservation. In this study we tried to identify a subset of patients who might be treated with a further conservative procedure, allowing a good local control. The most important finding of this analysis is that patients with a small (<2 cm) and late IBTR (>48 months) have a 5 years cumulative incidence of 12.8%. On the other hand, nine of the 16 patients with tumour >2 cm had a further IBTR after a second conservative surgery. These results, even if coming from a relatively small cohort of patients with a limited follow-up, in our opinion, are logical. A small relapse (<2 cm) offers the possibility of an acceptable cosmetic outcome and usually mirrors an early diagnosis. Moreover, early IBTR has been reported to be a worse prognostic factor [3–6] and the time interval between primary tumour and IBTR might be considered as a surrogate marker of aggressiveness. In fact, the local reappearance of breast cancer is usually not an innocent
original article
Annals of Oncology
Table 3. Multivariate analysis IBTR characteristics
Local-disease- Disease-free Overall free survival, survival, HR survival, HR (95% CI) (95% CI) HR (95% CI)
Size of tumour >2 cm Time to IBTR £48 months Oestrogen receptors absent Ki-67 ‡20%
2.8 1.6 1.4 1.4
(1.2–6.2) (0.8–3.2) (0.7–3.0) (0.6–2.9)
1.4 2.1 1.4 1.7
(0.7–2.9) (1.2–3.6) (0.8–2.4) (1.0–3.1)
1.1 2.2 2.5 2.5
(0.3–3.3) (0.8–6.0) (1.1–6.0) (0.8–7.8)
Hazard ratios (HR) and 95% confidence intervals (CI) are calculated using Cox proportional hazards model. IBTR, ipsilateral breast tumour recurrence.
Table 4. Local-disease-free survival stratified by tumour size and time to relapse
Events (% 5 years 8 (12.8) cumulative incidence) At risk 64
Tumour size Tumour £2 cm and size time to IBTR >2 cm £48 months 17 (30.1) 71
P valuea
9 (72.1) 0.003 16
Information on tumour size was missing for 10 patients. a Differences in survival between strata are tested using the log-rank test. IBTR, ipsilateral breast tumour recurrence.
Figure 2. Local-disease-free survival.
event, since the relative risk of death related to breast cancer is estimated to increase by a factor of 3.4–4.6 in patients who develop IBTR compared with patients who do not [6]. These findings were confirmed by a recent paper by National Surgical Adjuvant Breast and Bowel Project (NSABP) in which OS at 5 years for patients with IBTR was 59.9%, and the HR for mortality associated with IBTR was 2.58 [7]. Only five studies have been published evaluating the outcome of patients treated with a further conservative procedure alone after IBTR [8–12], reporting a local recurrence rate appearing to be on average 35%, which is similar to the rate of IBTR in
Volume 18 | No. 3 | March 2007
references 1. Veronesi U, Mariani L, Greco M et al. Twenty year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227–1232. 2. Fisher B, Anderson S, Bryant J et al. Twenty year follow-up of a randomised study comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233–1241. 3. Whelan T, Clark R, Roberts R et al. Ipsilateral breast tumour recurrence postlumpectomy is predictive of subsequent mortality: results from a randomized trial. Investigators of the Ontario Clinical Oncology Group. Int J Radiat Oncol Biol Phys 1994; 30: 11–16. 4. Doyle T, Schultz DJ, Peters C et al. Long-term results of local recurrence after breast conservation treatment for invasive breast cancer. Int J Radiat Oncol Biol Phys 2001; 51: 74–80.
doi:10.1093/annonc/mdl424 | 471
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Tumour size £2 cm and time to IBTR >48 months
patients treated by BCS without postoperative radiotherapy. Re-irradiation of the surgical bed after IBTR was described in a few papers [13–16] with acceptable cosmetic results and a limited number of major local complications. We agree with Kuerer et al. [17] that local control might be further ameliorated, promoting the use of partial breast irradiation after a second conservative procedure. At the European Institute of Oncology in Milan, we are now accumulating prospective experience with electron intraoperative therapy administered at the time of surgery in patients undergoing breast conservation for IBTR. This technique offers the enormous advantage of delivering the dose of radiotherapy directly over the tumour bed and under the visual control of the surgeon, sparing the skin and thereby avoiding complications of the superficial tissues [18]. Data arising from the study might be helpful in initiating the discussion between patients and physicians and in integrating the decision-making process when planning the type of surgery for an IBTR. In addition to the risk of local relapse, there are several issues to be addressed: first, a careful preoperative work-up must be carried out in order to rule out multicentricity and to ensure which patients are appropriate candidates for breast conservation. In our institution, we routinely use breast US in order to integrate mammography, and MR is carried out only in a few selected cases. In fact, we consider breast US reliable in the hands of very experienced operators. Nevertheless, we acknowledge that in some patients MR might be very helpful in order to decide the type of treatment. Secondly, the final expected cosmetic result should be discussed. Finally, we would like to underline the importance of the preference of the patients and their desire for breast conservation which should be acknowledged and respected as far as possible. In some situations, mastectomy is simply unavoidable because of the tumour/breast ratio, the presence of multicentricity or the poor expected cosmetic result. Mastectomy, however, remains an irreversible mutilation which permanently alters the feminine image. Even with the best results, immediate breast reconstruction may sometimes lead to severe psychological trauma and to unavoidable consequences in social, sexual and everyday life. We are convinced that in motivated patients with IBTR and a good estimated local control, according to recurrent tumour size and time to IBTR, breast conservation might be carried out.
original article
472 | Gentilini et al.
12. Salvadori B, Marubini E, Miceli R et al. Reoperation for locally recurrent breast cancer in patients previously treated with conservative surgery. Br J Surg 1999; 86: 84–87. 13. Recht A, Schnitt SJ, Connolly JL et al. Prognosis following local or regional recurrence after conservative surgery and radiotherapy for early stage breast carcinoma. Int J Radiat Oncol Biol Phys 1989; 16: 3–9. 14. Maulard C, Housset M, Brunel P et al. Use of perioperative or split-course interstitial brachytherapy techniques for salvage irradiation of isolated local recurrences after conservative management of breast cancer. Am J Clin Oncol 1995; 18: 348–352. 15. Deutsch M. Repeat high-dose external beam irradiation for in-breast tumour recurrence after previous lumpectomy and whole breast irradiation. Int J Radiat Oncol Biol Phys 2002; 53: 687–691. 16. Resch A, Fellner C, Mock U et al. Locally recurrent breast cancer: pulse dose rate brachytherapy for repeat irradiation following lumpectomy—a second chance to preserve the breast. Radiology 2002; 225: 713–718. 17. Kuerer HM, Arthur DW, Haffty BG et al. Repeat breast-conserving surgery for in-breast local breast carcinoma recurrence. The potential role of partial breast irradiation. Cancer 2004; 100: 2269–2280. 18. Veronesi U, Orecchia R, Luini A et al. Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery: experience with 590 cases. Ann Surg 2005; 242: 101–106.
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5. Haffty BG, Reiss M, Beinfield M et al. Ipsilateral breast tumour recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse. J Clin Oncol 1996; 14: 52–57. 6. 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: 19–27. 7. Wapnir IL, Anderson SJ, Mamounas EP et al. Prognosis after ipsilateral breast tumour recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 2006; 24: 2028–2037. 8. Kurtz JM, Jacquemier J, Amalric R et al. Is breast conservation after local recurrence feasible? Eur J Cancer 1991; 27: 240–244. 9. Abner AL, Recht A, Eberlein T et al. Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 1993; 11: 44–48. 10. Dalberg K, Mattsson A, Sandelin K et al. Outcome of treatment for ipsilateral breast tumour recurrence in early-stage breast cancer. Breast Cancer Res Treat 1998; 49: 69–78. 11. Voogd AC, van Tienhoven G, Peterse HL et al. Local recurrence after breast conservation therapy for early stage breast carcinoma: detection, treatment, and outcome in 266 patients. Dutch Study Group on Local Recurrence after Breast Conservation (BORST). Cancer 1999; 85: 437–446.
Annals of Oncology
Annals of Oncology 18: 468–472, 2007 doi:10.1093/annonc/mdl424 Published online 8 December 2006
When can a second conservative approach be considered for ipsilateral breast tumour recurrence? O. Gentilini1*, E. Botteri2, N. Rotmensz2, B. Santillo2, N. Peradze1, R. C. Saihum1, M. Intra1, A. Luini1, V. Galimberti1, A. Goldhirsch3 & U. Veronesi4 1 Division of Breast Surgery, 2Division of Epidemiology and Biostatistics, 3Department of Medical Oncology, 4Scientific Director, European Institute of Oncology, Milan, Italy
Received 30 June 2006; revised 16 October 2006; accepted 17 October 2006
(IBTR) after breast-conserving surgery (BCS).
original article
Patients and methods: One hundred and sixty-one patients with invasive IBTR who underwent a second conservative approach were retrospectively evaluated in order to describe prognosis, determine predictive factors of outcome and select the subset of patients with the best local control. Results: Fifty-seven patients (35.4%) relapsed after IBTR. Thirty-four patients (21.1%) had further in-breast recurrences and four patients (2.5%) had skin relapses. Five years cumulative incidence of local relapse was 31.4%. Twenty-four patients (17.8%, 5 years cumulative incidence) died during the follow-up. At the multivariate analysis, recurrent tumour size >2 cm was found to affect local-disease-free survival [hazard ratio (HR): 2.8, 95% confidence interval (CI) 1.2–6.2], whereas Ki-67 ‡20% and time to relapse £48 months were associated with disease-free survival (HR: 1.7, 95% CI 1.0–3.1, and HR: 2.1, 95% CI 1.2–3.6, respectively). Absence of oestrogen receptors affected overall survival (HR: 2.5, 95% CI 1.1–6.0). Among 64 patients with recurrent tumour £2 cm and time to IBTR >48 months, eight (12.8%, 5 years cumulative incidence) had further local relapses. Conclusions: Some patients with IBTR might receive a second BCS, especially when a good local control can be estimated (small recurrent tumour, late relapse), also taking into account patients’ preference. Key words: breast-conserving surgery, breast tumour, ipsilateral breast tumour recurrence
background Breast conservation is considered the treatment of first choice for early breast cancer worldwide, with a similar long-term outcome to mastectomy [1, 2]. Nevertheless, a minority of patients treated conservatively will develop ipsilateral breast tumour reappearance (IBTR) [1]. This event may in some way be considered by both physicians and patients to represent a failure of the conservative approach. In addition, relapse provokes serious anxiety in the patient, and so far, the vast majority of such women have undergone mastectomy, thus frustrating the objective of conservative surgery. Many women, however, are diagnosed with small and early-detected IBTR, which from a technical point of view might be managed with a new conservative procedure. The aim of this study was to retrospectively evaluate prognosis for patients with IBTR after breast conservation who were treated by second conservative surgery, to determine whether any predictive factors of outcome could be identified, *Correspondence to: Dr O. Gentilini, Division of Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489376; Fax: +39-02-57489780; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
and to select the subset of patients who are the best candidates for a second conservative approach.
patients and methods From April 1997 to December 2004, 12 357 patients were operated on and prospectively entered into the database of the European Institute of Oncology in Milan. Two hundred and eighty-eight consecutive patients with invasive operable IBTR as a first event and no evidence of synchronous metastatic disease were identified. For the treatment of primary cancer, all patients underwent breast-conserving surgery (BCS) followed by conventional external radiotherapy over the breast and locoregional radiotherapy whenever appropriate. Ninety-nine were operated on in our institute for the primary cancer, whereas 189 were initially operated on at a different hospital and then referred to our institute for the treatment of IBTR. At occurrence of IBTR, all patients underwent physical examination, complete staging [bone scan, chest X-ray, liver ultrasound (US) or computed tomography (CT) scan], mammography and breast US to rule out multicentricity. Magnetic resonance (MR) of the breast was carried out only in a few selected patients. One hundred and twenty-seven of 288 patients received mastectomy (44.1%), whereas 161 patients (55.9%) after a thorough discussion with the
Downloaded from http://annonc.oxfordjournals.org/ at New York University on July 12, 2015
Background: Mastectomy is considered the treatment of choice in patients with ipsilateral breast tumour recurrence
original article
Annals of Oncology
operating surgeon, underwent a further conservative approach (wide local excision with microscopic clear margins) and represent the population of the study. After the surgical treatment of IBTR, all the patients were discussed within the multidisciplinary meeting attended by surgeons, medical oncologists, radiation oncologists and pathologists and received adjuvant treatment according to staging and biological features. None of the patients received further radiation therapy after the treatment of IBTR. Median age of patients at the occurrence of IBTR was 53 years (range 24– 95). Median time to relapse was 46 months (range 4–284). Median followup was 44 months (range 4–107). One patient died from another primary tumour (pancreatic cancer) 4 months after surgery for IBTR, representing the shortest period of observation. Patients were usually followed up by physical examination every 6 months and mammography with or without breast US every year. In cases with symptoms or when clinically indicated, bone scan, chest X-ray, liver US or CT scan were carried out.
Primary end points were local-disease-free survival, disease-free survival (DFS) and overall survival (OS). Local-disease-free survival was calculated from the first IBTR to any local recurrence (i.e. second IBTR or skin recurrence). DFS was calculated from the date of first IBTR to any relapse, second primary cancer, contralateral breast cancer recurrence or death, whichever occurred first. OS was defined as the time interval from first IBTR to death from any cause. The OS and local-disease-free survival were plotted using the Kaplan– Meier method. The log-rank test was used to assess survival differences between groups in the univariate analysis. Multivariate Cox proportional hazards regression models were used to identify the prognostic independent clinico-pathological features associated with survival. All analyses were carried out with the SAS software (SAS Institute, Cary, NC). All tests were two-sided.
results Table 1 represents patients’ characteristics at presentation of primary breast cancer and at the occurrence of IBTR. In regards to further local relapses, 34 patients (21.1%) experienced a further in-breast recurrence and four patients (2.5%) had a skin relapse. Five years cumulative incidence of local relapse was 31.4%. Considering other types of events, 15 patients (9.3%) developed distant metastases, one patient (0.6%) had both local and distant metastases, one patient had a contralateral breast tumour, one patient had metastases in regional nodes and one patient experienced another primary tumour. Twenty-four patients (14.9%) died during the follow-up, with an OS at 5 years of 82.2% (Figure 1). At the univariate analysis (Table 2), recurrent tumour size >2 cm was found to be associated with poor local-disease-free survival (P value 0.002), whereas time to IBTR £48 months and absence of oestrogen receptors (ER) were close to reaching statistical significance (P value 0.062 both). For the DFS, time to relapse was the most important factor (P value 0.003), with recurrent tumour size, hormonal receptor status and Ki-67 also reaching statistical significance. Absence of ER was the most important variable affecting OS (P value 0.001) along with absence of progesterone receptors (P value 0.03) and Ki-67 ‡20 (P value 0.02). At the multivariate analysis (Table 3), recurrent tumour size >2 cm was found to independently affect local-disease-free
Volume 18 | No. 3 | March 2007
Presentation at primary cancer Age (years)
Size of tumour (cm) Regional lymph nodes involved
Histotype
Presentation at first IBTR Age (years)
Time to IBTR (months)
Size of tumour (cm)
Histotype
Oestrogen receptors Progesteron receptors Her2/neu Ki-67 Vascular invasion Multifocality
Classification
No. (%)a
<35 35–50 51–60 >60 £2 >2 0 1–3 4–9 10+ Ductal Lobular Other
19 80 34 28 107 41 88 34 11 5 129 19 11
(11.7) (49.7) (21.1) (17.4) (72.3) (27.7) (63.8) (24.6) (8.0) (3.6) (81.2) (11.9) (6.9)
<35 35–50 51–60 >60 £24 25–48 >48 £0.5 0.6–1.0 1.1–1.5 1.6–2.0 >2.0 Ductal Lobular Other Present Present Overexpressed <20% Present Present
7 61 51 42 36 55 70 16 45 54 20 16 128 13 20 125 101 19 64 26 16
(4.3) (37.9) (31.7) (26.1) (22.4) (34.2) (43.5) (10.6) (29.8) (35.8) (13.2) (10.6) (79.5) (8.1) (12.4) (78.1) (63.5) (12.2) (41.6) (17.6) (10.5)
a
Information missing for a few patients. IBTR, ipsilateral breast tumour recurrence.
Figure 1. Overall survival.
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statistical methods
Table 1. Patients’ characteristics
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survival [HR: 2.8, 95% confidence interval (CI) 1.2–6.2], whereas Ki-67 ‡20% and time to relapse <48 months were found to be associated with DFS (HR: 1.7, 95% CI 1.0–3.1, and HR: 2.1, 95% CI 1.2–3.6, respectively). Absence of ER affected OS (HR: 2.5, 95% CI 1.1–6.0). In Table 4, local-disease-free survival stratified by tumour size and time to relapse is shown. Among the 64 patients with IBTR <2 cm and time to relapse >48 months, eight (12.8%, 5 years cumulative incidence) had a further local relapse with a significantly better local-disease-free survival (P value 0.003). Figure 2 represents local-disease-free survival after the second conservative surgery.
conclusions
Table 2. Univariate analysis: clinico-pathologic features of ipsilateral breast tumour recurrence associated with survival Classification
All patients Age (years) £50 >50 Size of tumour (cm) £2 >2 Time to IBTR (months) £48 >48 Histotype Ductal Lobular Oestrogen receptors Present Absent Progesteron receptors Present Absent Her2/neu Not overexpressed Overexpressed Ki-67 (%) <20 ‡20 Vascular invasion Present Absent Multifocality Present Absent
Local-disease-free survivala Events (% 5 years P valuec cumulative incidence)
Disease-free survivalb Events (% 5 years cumulative incidence)
161
38 (31.4)
66 (50.8)
68 93
20 (39.8) 18 (24.7)
0.198
32 (55.9) 34 (47.2)
0.316
14 (25.8) 10 (12.2)
0.150
135 16
25 (22.4) 9 (71.2)
0.002
50 (46.3) 11 (75.6)
0.048
19 (17.9) 4 (26.6)
0.370
87 74
26 (41.6) 12 (18.0)
0.062
47 (61.6) 19 (34.7)
0.003
18 (22.5) 6 (11.5)
0.068
128 13
29 (30.6) 3 (27.1)
0.793
53 (52.0) 6 (50.6)
0.405
22 (20.4) 1 (14.3)
0.485
125 35
25 (26.2) 12 (48.8)
0.062
44 (43.6) 21 (72.3)
0.016
11 (13.2) 12 (34.1)
0.001
101 58
24 (31.9) 13 (27.9)
0.854
37 (45.9) 28 (58.9)
0.107
10 (14.2) 13 (25.6)
0.038
134 19
28 (28.5) 4 (26.4)
0.643
49 (46.4) 10 (57.9)
0.086
16 (15.7) 4 (30.4)
0.183
64 90
11 (18.0) 25 (40.9)
0.082
18 (33.6) 44 (61.4)
0.012
4 (11.5) 18 (22.8)
0.020
26 121
7 (36.3) 25 (26.9)
0.368
13 (57.3) 47 (49.1)
0.280
5 (24.3) 18 (17.8)
0.674
16 136
4 (44.3) 31 (30.1)
0.518
9 (67.5) 53 (48.7)
0.071
3 (20.5) 20 (18.0)
0.503
No. at risk
P valuec
Overall survival Events (% 5 years cumulative incidence)
P valuec
24 (17.8)
a
Events: ipsilateral breast tumour or skin recurrence. Events: second relapses or death without second relapses. c Differences in survival between strata are tested using the log-rank test. IBTR, ipsilateral breast tumour recurrence. b
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So far, IBTR after breast conservation has been dogmatically treated by mastectomy, even in patients with small recurrences which might have been managed conservatively. We believe that
the occurrence of IBTR should not be considered per se a failure of the conservative approach and that in some patients there exists the possibility to successfully repeat breast conservation. In this study we tried to identify a subset of patients who might be treated with a further conservative procedure, allowing a good local control. The most important finding of this analysis is that patients with a small (<2 cm) and late IBTR (>48 months) have a 5 years cumulative incidence of 12.8%. On the other hand, nine of the 16 patients with tumour >2 cm had a further IBTR after a second conservative surgery. These results, even if coming from a relatively small cohort of patients with a limited follow-up, in our opinion, are logical. A small relapse (<2 cm) offers the possibility of an acceptable cosmetic outcome and usually mirrors an early diagnosis. Moreover, early IBTR has been reported to be a worse prognostic factor [3–6] and the time interval between primary tumour and IBTR might be considered as a surrogate marker of aggressiveness. In fact, the local reappearance of breast cancer is usually not an innocent
original article
Annals of Oncology
Table 3. Multivariate analysis IBTR characteristics
Local-disease- Disease-free Overall free survival, survival, HR survival, HR (95% CI) (95% CI) HR (95% CI)
Size of tumour >2 cm Time to IBTR £48 months Oestrogen receptors absent Ki-67 ‡20%
2.8 1.6 1.4 1.4
(1.2–6.2) (0.8–3.2) (0.7–3.0) (0.6–2.9)
1.4 2.1 1.4 1.7
(0.7–2.9) (1.2–3.6) (0.8–2.4) (1.0–3.1)
1.1 2.2 2.5 2.5
(0.3–3.3) (0.8–6.0) (1.1–6.0) (0.8–7.8)
Hazard ratios (HR) and 95% confidence intervals (CI) are calculated using Cox proportional hazards model. IBTR, ipsilateral breast tumour recurrence.
Table 4. Local-disease-free survival stratified by tumour size and time to relapse
Events (% 5 years 8 (12.8) cumulative incidence) At risk 64
Tumour size Tumour £2 cm and size time to IBTR >2 cm £48 months 17 (30.1) 71
P valuea
9 (72.1) 0.003 16
Information on tumour size was missing for 10 patients. a Differences in survival between strata are tested using the log-rank test. IBTR, ipsilateral breast tumour recurrence.
Figure 2. Local-disease-free survival.
event, since the relative risk of death related to breast cancer is estimated to increase by a factor of 3.4–4.6 in patients who develop IBTR compared with patients who do not [6]. These findings were confirmed by a recent paper by National Surgical Adjuvant Breast and Bowel Project (NSABP) in which OS at 5 years for patients with IBTR was 59.9%, and the HR for mortality associated with IBTR was 2.58 [7]. Only five studies have been published evaluating the outcome of patients treated with a further conservative procedure alone after IBTR [8–12], reporting a local recurrence rate appearing to be on average 35%, which is similar to the rate of IBTR in
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references 1. Veronesi U, Mariani L, Greco M et al. Twenty year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227–1232. 2. Fisher B, Anderson S, Bryant J et al. Twenty year follow-up of a randomised study comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233–1241. 3. Whelan T, Clark R, Roberts R et al. Ipsilateral breast tumour recurrence postlumpectomy is predictive of subsequent mortality: results from a randomized trial. Investigators of the Ontario Clinical Oncology Group. Int J Radiat Oncol Biol Phys 1994; 30: 11–16. 4. Doyle T, Schultz DJ, Peters C et al. Long-term results of local recurrence after breast conservation treatment for invasive breast cancer. Int J Radiat Oncol Biol Phys 2001; 51: 74–80.
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Tumour size £2 cm and time to IBTR >48 months
patients treated by BCS without postoperative radiotherapy. Re-irradiation of the surgical bed after IBTR was described in a few papers [13–16] with acceptable cosmetic results and a limited number of major local complications. We agree with Kuerer et al. [17] that local control might be further ameliorated, promoting the use of partial breast irradiation after a second conservative procedure. At the European Institute of Oncology in Milan, we are now accumulating prospective experience with electron intraoperative therapy administered at the time of surgery in patients undergoing breast conservation for IBTR. This technique offers the enormous advantage of delivering the dose of radiotherapy directly over the tumour bed and under the visual control of the surgeon, sparing the skin and thereby avoiding complications of the superficial tissues [18]. Data arising from the study might be helpful in initiating the discussion between patients and physicians and in integrating the decision-making process when planning the type of surgery for an IBTR. In addition to the risk of local relapse, there are several issues to be addressed: first, a careful preoperative work-up must be carried out in order to rule out multicentricity and to ensure which patients are appropriate candidates for breast conservation. In our institution, we routinely use breast US in order to integrate mammography, and MR is carried out only in a few selected cases. In fact, we consider breast US reliable in the hands of very experienced operators. Nevertheless, we acknowledge that in some patients MR might be very helpful in order to decide the type of treatment. Secondly, the final expected cosmetic result should be discussed. Finally, we would like to underline the importance of the preference of the patients and their desire for breast conservation which should be acknowledged and respected as far as possible. In some situations, mastectomy is simply unavoidable because of the tumour/breast ratio, the presence of multicentricity or the poor expected cosmetic result. Mastectomy, however, remains an irreversible mutilation which permanently alters the feminine image. Even with the best results, immediate breast reconstruction may sometimes lead to severe psychological trauma and to unavoidable consequences in social, sexual and everyday life. We are convinced that in motivated patients with IBTR and a good estimated local control, according to recurrent tumour size and time to IBTR, breast conservation might be carried out.
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