| | Impact of the boost dose of 10 Gy versus 26Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trialReceived 12 May 2008; received in revised form 1 July 2008; accepted 16 July 2008. published online 19 August 2008. Abstract PurposeTo assess the impact of the boost dose in patients with involved surgical margins. ResultsThe median age at randomisation was 54 years. Thirty-seven patient initially relapsed locally. At 10 years, the cumulative incidence of local recurrence was 17.5% (95% CI: 10.4–24.6%) versus 10.8% (95% CI: 5.2–16.4%) for the low and high boost dose groups, respectively (HR=0.83, 95% CI: 0.43–1.57, Gray p>0.1). Overall, 64 patients have died (25.5%), 47 of them of breast cancer, without a difference in duration of survival between the two groups (HR=0.97, 95% CI=0.59–1.5, p>0.1). Severe fibrosis was palpated in the breast in 1% versus 5% and in the boost area in 3% versus 13% in the low and high boost dose groups, respectively. ConclusionsThere was no statistically significant difference in local control or survival between the high boost dose of 26Gy and the low boost dose of 10Gy in patients with microscopically incomplete excision of early breast cancer. Fibrosis, however, was noted significantly more frequently in cases treated with the high boost dose. Breast-conserving therapy (BCT) is considered the standard of care for stage I and II breast cancer patients, with equivalent survival compared to mastectomy [1], [2], [3]. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis confirmed the need for radiotherapy after lumpectomy, by showing that breast irradiation reduced the 5-year local recurrence rate from 26% to 7% [4]. In the EORTC (European Organisation for Research and Treatment of Cancer) trial 10801 that compared BCT with mastectomy, two major limitations were identified, despite similar survival rates and a limited difference in local control between the two treatment arms [3]. First, a significant proportion of the patients experienced severe fibrosis that resulted in a poor cosmetic outcome because of the high radiation dose given [5]; second, major differences in local control were observed between the treating institutes, which could not be explained by patient selection [6]. Meanwhile, Van Limbergen et al. demonstrated the dose-dependency of local control, suggesting a decrease in the local failure rate by a factor of two for every 15Gy increase in dose [7]. Against this background, the EORTC launched a subsequent prospective randomised trial (EORTC 22881-10882 “boost” trial), investigating the relevance of a boost dose to the primary tumour site after lumpectomy and whole breast irradiation (50Gy in 25 fractions over 5 weeks). In this randomised phase III trial patients who underwent a microscopically complete tumour excision received either a boost or no boost. The boost dose was 16Gy, because of the large proportion of patients who developed fibrosis with 25Gy boost in the earlier trial. The 10-year results demonstrated that this boost dose reduced the local recurrence rate by 41% (10.2% versus 6.2%), without a difference in survival [8]. For many years, the association between positive resection margins and local recurrence after BCT has been controversial but, in general, they are considered as a relevant poor risk factor for developing a local recurrence after BCT [7], [9], [10]. Whereas the optimal resection margin is uncertain, surgery should always aim at removing the whole tumour including a margin of surrounding breast issue. That this is not always successful is illustrated in the EORTC “boost” trial, where in about 15% of the cases the resection margins of the first lumpectomy turned out to be involved by tumour. In most cases, a second excision can make the resection complete but often surgical factors and the expected cosmetic outcome make this impossible. Whereas a mastectomy is often proposed to the patients, this is not always accepted and might even be considered as unnecessary. A large number of factors have an influence on the risk of an incomplete lumpectomy, including patient and tumour related factors such as the size and location of the tumour within the breast, the volume of the breast and thereby the amount of normal breast issue surrounding the tumour that can be removed, and histological factors with especially a high risk for invasive lobular carcinoma and in the presence of an extensive intraductal component [11]. Surgical factors might play an important role as well, including the experience of the surgeon and the availability of technical solutions to guide the lumpectomy especially in the case of smaller not palpable lesions. Whether the higher local recurrence risk after an incomplete tumour excision can be completely counterbalanced by increasing the boost dose has not been demonstrated clearly. Therefore, we randomised in the EORTC 22881-10882 “boost” trial patients with a microscopically incomplete resection of the primary tumour (as stated by the local pathologist) between a low boost dose of 10Gy, supposedly associated with a better cosmetic outcome, and a high boost dose of 26Gy, supposedly achieving a better clinical control at the cost of possible increased fibrosis and less satisfactory cosmetic outcome. The trial objectives for this subgroup were therefore primarily to assess the impact on local control and how much the potential difference in local control is counterbalanced by an increased fibrosis. Patients and methods  Patients up to 70 years with T1-2, N0-1, and M0 breast cancer were eligible for this trial [12]. Patients with pure carcinoma in situ (CIS), multiple tumour foci in more than one quadrant, a history of other malignant disease, a WHO performance score ⩾2, residual micro-calcifications on mammography or gross residual disease in the breast after lumpectomy (unless re-excision had been performed) were ineligible. Oral informed consent was obtained according to EORTC guidelines and the local and national rules of the participating centres. Surgery preceded referral for radiotherapy and consisted of excision of the primary tumour, with a 1-cm margin of macroscopically normal tissue, and an axillary lymph node dissection. Any removal of additional breast tissue after the excision of the primary tumour was scored as a re-excision, whether it was performed during the same session or later. The resection margins were evaluated by the local pathologist for the presence of invasive carcinoma and for DCIS, without any further specification of the extent of the involvement. Patients with gross tumour involvement or with residual micro-calcifications on a postoperative mammography were not eligible. A subset of 1725 patients had a central pathology review of their slides. Patients with involved axillary lymph nodes received adjuvant systemic therapy, consisting of chemotherapy for pre-menopausal patients and tamoxifen for postmenopausal patients. Radiotherapy started not later than 9 weeks after lumpectomy, unless adjuvant chemotherapy was given first. Irradiation of the whole breast was performed using two tangential megavoltage photon beams (photons or cobalt-60). A total dose of 50Gy over a 5-week period, with a dose of 2Gy per fraction, was delivered at the intersection of the central axes of the beams, according to the ICRU 50 report [13]. Two off-axis dose distributions in the tumour excision area and cranial and caudal border planes had to be calculated as well. The boost dose had to be specified at the centre of the surgical tumour bed. This dose remained fixed and independent of the dose actually delivered to the boost area during the external irradiation of the whole breast. The boost dose had to be delivered with electrons or tangential fields given in daily fractions of 2Gy, or with an iridium-192 implant at a dose rate of 0.5Gy per hour. The boost volume was described as the site of the primary tumour with a margin of 1.5cm to the field borders after a complete lumpectomy and of 3cm after an incomplete resection or in the presence of an extensive intraductal component [14]. An intensive Quality Assurance programme for radiotherapy was organised to ensure that the treatment was delivered according to the guidelines described in the protocol in all centres [15]. Randomisation was done after surgery and centrally at the EORTC Head Quarters using the minimisation technique [16]. Treatment allocation was balanced with respect to age, menopausal status, presence of extensive DCIS (when 10 or more ducts were involved, the DCIS component was classified as such), clinical tumour size, nodal status, and institute where they received radiotherapy. The patients with complete tumour excision were allocated no boost or 16Gy boost, the patients with incomplete excision were separately allocated a 10Gy boost or a 26Gy boost. All analyses were carried out according to the intent-to-treat policy, i.e. all randomised patients are included in the analyses in the arm they were assigned by randomisation. Time to local recurrence was calculated from the date of randomisation to the date of recurrence. Local recurrences in the breast as the first failure were analysed. Data for patients who remained free of local disease were censored at the date of last visit, but any other failure as the first event was considered as a competing risk. Survival and local failure rates were estimated by Kaplan–Meier and by cumulative incidence, respectively [17], [18]. The 2-sided significance level was set at 0.05. Treatment effects are summarised by the hazard ratio estimated from unadjusted Cox regression models and its associated 95% confidence interval. In the original protocol, 660 patients with incomplete excision were planned to be recruited and followed for 10 years, with the aim to exclude a loss of 5% or more in the 10-year local control rate with the low boost dose compared to the high boost dose, at the 1-sided 5% significance level. The second objective was to evaluate a possible difference in the development of fibrosis in the treated breast. However, the study duration was driven by the complete resection group and when the trial closed only 251 patients with an incomplete excision had been entered. Results The trial recruited a total of 5569 patients from 1989 to 1996. Despite this long period, only 251 patients with a microscopically incomplete excision followed by the whole breast irradiation to 50Gy in 5 weeks were randomised between a boost dose of 10Gy (126 patients) versus 26Gy (125 patients). The median follow-up in this patient group was 11.3 years. Tumour and surgical characteristics of the patients were similar in the two groups (Table 1, Table 2): the median age was 54 year old and 42% were pre-menopausal, 87% presented with cN0 tumours and 65% with pN0. There were no marked differences between the groups with respect to the whole breast irradiation (Table 3). Five patients were not irradiated (3 in the 10Gy group and 2 in the 26Gy group), due to a mastectomy, tumour progression, treatment refusal and (twice) administrative reasons. Four cases in the 10Gy group were entered as having an incomplete excision, but were later deemed to have a complete excision and did not receive a boost. In the 10Gy group, 12 patients received an interstitial boost (10%) compared to 34 (28%) patients in the 26Gy group. Fourteen percent of the patients received only adjuvant chemotherapy, 19% were given only adjuvant tamoxifen and 7% received both, similarly distributed in the two randomisation groups Table 4. | | |  | Variable | Randomised treatment | |
|---|
| 10Gy (n=126) n (%) | 26Gy (n=125) n (%) | |
|---|
| Clinical T | | | T1 | 63 (50.0) | 71 (56.8) | | | T2 | 62 (49.2) | 53 (42.4) | | | T3 | 1 (0.8) | 1 (0.8) | | | | | | Pathological tumour diameter | | | <10mm | 25 (19.8) | 26 (20.8) | | | 10–20 | 58 (46.0) | 64 (51.2) | | | >20mm | 37 (29.4) | 33 (26.4) | | | Missing | 6 (4.8) | 2 (1.6) | | | | | | Histology | | | Invasive ductal | 96 (76.2) | 98 (78.4) | | | Invasive lobular | 18 (14.3) | 17 (13.6) | | | Other | 12 (9.5) | 10 (8.0) | | | | | | Hormone receptors | | | ER+, PG+ | 49 (38.9) | 46 (36.8) | | | ER+, PR− | 19 (15.1) | 15 (12.0) | | | ER−, PR+ | 6 (4.8) | 2 (1.6) | | | ER−, PR− | 15 (11.9) | 14 (11.2) | | | Missing | 37 (29.4) | 48 (38.4) | | | | | | Clinical N | | | N0 | 106 (84.1) | 107 (85.6) | | | N1 | 15 (11.9) | 16 (12.8) | | | NX | 4 (3.2) | 1 (0.8) | | | Missing | 1 (0.8) | 1 (0.8) | | | | | | Pathological N | | | 0 | 79 (62.7) | 83 (66.4) | | | 1–3 | 32 (25.4) | 32 (25.6) | | | 4+ | 14 (11.1) | 9 (7.2) | | | Missing | 1 (0.8) | 1 (0.8) | | | | |
| | | | Variable | Randomised treatment | |
|---|
| 10Gy (n=126) n (%) | 26Gy (n=125) n (%) | |
|---|
| Second resection performed | 18 (14.3) | 18 (14.4) | | | | | | Breast complications | 12 (9.5) | 16 (12.8) | | | Haematoma | 11 (8.7) | 14 (11.2) | | | Oedema | 5 (4.0) | 7 (5.6) | | | Infection | 1 (0.8) | 2 (1.6) | | | Seroma | 3 (2.4) | 5 (4.0) | | | | | | Excised volume (cc) | | | Median | 75.0 | 81.0 | | | Range | 5.3–576.0 | 2.5–635.3 | | | | |
| | | | Variable | Randomised treatment | |
|---|
| 10Gy (n=123) | 26Gy (n=123) | |
|---|
| Dose at ICRU point (Gy) | | | Median | 50.0 | 50.0 | | | Range | 50.0–52.8 | 49.8–54.0 | | | | | | Dose at primary tumour bed (Gy) | | | Median | 50.0 | 50.0 | | | Range | 45.0–56.0 | 45.0–57.0 | | | | | | Radiation quality | | | Cobalt-60 | 43 (35.0) | 39 (31.7) | | | Photons | 80 (65.0) | 81 (65.9) | | | Cobalt-60 and photons | 0 (0.0) | 3 (2.4) | | | | | | Duration of radiotherapy (days) | | | Median | 35 | 35 | | | Range | 31–50 | 30–53 | | | | |
| | | | Variable | Randomised treatment | |
|---|
| 10Gy (n=123) | 26Gy (n=123) | |
|---|
| Boost received? (n (%)) | | | No boost | 4 (3.3) | 0 (0.0) | | | External boost | 107 (87.0) | 89 (72.4) | | | Electrons | 80 (74.8) | 69 (77.5) | | | Photons | 12 (11.2) | 11 (12.4) | | | Cobalt-60 | 15 (14.0) | 9 (10.1) | | | Interstitial boost | 12 (9.8) | 34 (27.6) | | | | | | External boost dose (Gy) | | | Median | 10.0 | 26.0 | | | Range | 9.0–23.5 | 10.0–26.0 | | | | | | Duration external boost (days) | | | Median | 6.0 | 17.0 | | | Range | 2.0–15.0 | 3.0–313.0 | | | | | | External boost volume (cc) | | | Median | 181.0 | 150.0 | | | Range | 42.0–1176.0 | 43.0–630.0 | | | | | | Duration interstitial boost (days) | | | Median | 20.5 | 43.0 | | | Range | 13.0–40.0 | 18.0–71.0 | | | | | | Interstitial boost dose (Gy) | | | Median | 10.0 | 25.0 | | | Range | 10.0–25.0 | 15.0–26.0 | | | | | | Reference dose rate (Gy/h) | | | Median | 0.5 | 0.5 | | | Range | 0.4–0.8 | 0.4–1.0 | | | | |
Ipsilateral breast recurrence occurred as the first failure in 20 of 126 versus 17 of 125 patients in the low and high dose boost groups, respectively. At 10 years, the cumulative incidence of local recurrence was 17.5% (95% CI: 10.4–24.6%) and 10.8% (95% CI: 5.2–16.4%) (HR=0.83, 95% CI: 0.43–1.57) (Fig. 1). In each group, 10 local recurrences occurred in the primary tumour bed, 2 in the scar, 1 after a 10Gy boost and 2 after a 25Gy boost were diffused and the remaining recurrences occurred outside of the original tumour area. The distribution of the occurrence of first events, occurring within 10 years of follow-up, is shown in Table 5. Of note, only one patient with the regional recurrence was reported to have later failed locally and only one patient was reported to have a local failure following a distant failure. Thirty-three patients died in the low dose group and 31 in the high dose group, of which 23 and 24 were due to breast cancer, respectively. Ten-year survival was similar in the two groups: 76.7% in the low boost group (95% CI: 68.0–83.3%) and 77.8% in the high boost group (95% CI: 69.0–84.3%) for HR=0.97 (95% CI: 0.59–1.58). | | | | Variable | Randomized treatment | |
|---|
| 10Gy (n=45) n (%) | 26Gy (n=42) n (%) | |
|---|
| Local relapse | 20 (44.4) | 13 (31.0) | | | Regional relapse | 1 (2.2) | 5 (11.9) | | | Distant failure | 19 (42.2) | 21 (50.0) | | | Contralateral breast cancer | 3 (6.7) | 3 (7.1) | | | Second primary tumour | 2 (4.4) | 0 (0.0) | | | | |
Fibrosis was scored by the treating physician on a 4 point scale (1=none, 2=minor, 3=moderate, 4=severe) at every follow-up visit separately for the whole breast and the boost area. The higher boost dose resulted in a significantly worse grade of fibrosis in both the whole breast and the boost area (Fig. 2). The cumulative incidence of severe fibrosis in the boost area or in the whole breast at 10-year was 14.4% after 26Gy (95% CI: 8.0–20.7%) versus 3.3% (95% CI: 1.1–6.5%) after 10Gy (Gray’s p=0.002). Moderate fibrosis was also more commonly observed in the 26Gy group, with a 10-year cumulative incidence of moderate fibrosis of 54.3% (95% CI: 45.4–63.3%) versus 24.0% (95% CI: 16.3–31.7%) with 10Gy boost (Gray’s p<0.0001). Discussion Local control In this patient group with incomplete tumour resection, the increase of the boost dose with 16Gy did not significantly decrease the local recurrence rate (p>0.1). However, the sample size was very limited (37 local failures); thus, the statistical power and the precision of the estimated effects are extremely poor. Hence, a dose response relationship in this patient subgroup could not be assessed, whereas this was the case for the completely resected patient group [8]. In comparison to our prospectively collected cohorts of patients with stage I and II breast cancer after a microscopically complete lumpectomy, the group with incomplete resection margins shows almost double the risk of local recurrence rate (15% versus 8% cumulative risk at 10 years), suggesting that incomplete resection margins are an adverse prognostic factor. This effect might partly be explained by the higher tumour stage in the patient group with an incomplete resection, 28% pT2 and 35% pN1 versus 20% and 21%, respectively, for the complete resection group. Our series is to our knowledge the only published prospective series entirely focused on incompletely resected tumours treated with BCT. Our results compare very favourably with the retrospective series of Schuck et al. who reviewed 489 patients (89 after mastectomy and 400 in the framework of BCT) without metastases that have been irradiated after surgery for primary breast cancer to 50Gy in 25 fractions with an electron boost of 10Gy in case of a microscopically incomplete resection. The only statistically significant risk factor for the local failure was a microscopically incomplete resection with corresponding 5-year local recurrence rates for microscopically incomplete and complete resections of 23.6% and 7.3% (p=0.01) [19]. The importance of involved resection margins in invasive lobular carcinoma is likely to be much less or even inexistent according to Van den Broek et al. who examined a population-based group of 416 patients treated with BCT. They showed no influence of the involvement of the resection margins on local control which was overall excellent and maybe even superior to that of invasive ductal carcinoma [11]. This is in agreement with the data suggesting that invasive lobular carcinoma could be more radiosensitive than invasive ductal carcinoma: five of seven patients with a stage T3 tumour treated with radiotherapy only had long-term local control after moderate doses of 51–60Gy [20]. The number of patients with invasive lobular carcinoma in our group (35 patients, 14%) was too small to draw any conclusion concerning this item. The importance of the status of the microscopic resection margin remains up to date unclear, with conflicting results on the local recurrence rate in several reports [21], [22], [23], [24]. In a subset of 1725 of the 5569 patients participating in the EORTC trial, a central pathology review was performed by HL Peterse [25]. The resection margin was negative in 73%, close (<2mm) in 21% and involved in 6% of the patients, respectively. In the multivariable analysis of the local failure, the resection margin was not statistically significant (p=0.48). These results are currently being further evaluated. Overall, it seems that the value of involvement of the resection margin as a poor risk factor for local control remains as yet unresolved. Limitations of the study In the late eighties, when the trial was designed, we believed that a large proportion of the patients eligible for the trial would have a microscopically incomplete lumpectomy. However, it soon appeared that the accrual of this type of patients was much less successful than that of completely resected patients and much less than originally anticipated. During the entire recruitment period, roughly only 5% of the participating patients had a microscopically incomplete resection. An explanation for this low recruitment may be that the completeness of the excision was seen as an important prerequisite to achieve local control in the framework of BCT, and the treatment offered in the trial might have been regarded as being possibly suboptimal, even in regard to a more mutilating surgical treatment. In effect, most patients underwent a second excision or even a mastectomy if the latter was not possible and were not entered in the trial. Indeed, in the completely resected group, 24.6% of the patients had a second excision after the first lumpectomy [8]. Even in our incompletely resected group, 14.3% of the patients had second surgery to remove supplementary breast tissue in an effort to obtain a complete removal of the tumour. Another possible explanation for the low rate of incomplete excisions might also relate to the quality of the local pathology report on the basis of which randomisation was performed. The definition of an incomplete excision in the protocol required the presence of tumour cells at the surgical resection margin. A more detailed description, as required nowadays, was not yet in use and cannot be reliably assessed retrospectively based on the material that is available. Moreover, details on the presence of DCIS were not collected either. It is very likely that the reporting of margin involvement in nowadays pathology reports have considerably improved, leading to a better estimation of the risks for the individual patient. With 37 events of local relapse, the sensitivity and statistical power to detect any realistic difference between groups is almost nil. The presented group of patients had, when compared to the 5318 patients after a microscopically complete lumpectomy randomised in the same trial, a somewhat higher tumour stage [8]. This may be because some physicians put less emphasis on local control in the presence of adverse risk factors for distant metastases. However, adjuvant systemic treatments were less commonly used in this study compared to nowadays standards. Much evidence emerged since 2000 showing a reduction of the risk of local relapse by a factor of about 2 when adjuvant systemic treatment is given [1], [28], [29]. While nowadays many more patients will receive chemotherapy and hormones, a microscopically incomplete lumpectomy may be another reason to advise this in patients that are not amenable to subsequent non ablative surgical approaches. We observed that an interstitial boost was used more frequently in the high boost dose group (27.6% versus 9.8%). This seems logical in view of the higher conformality offered by this approach, combined with the proportionally larger benefit with increasing doses. In the whole study, the use of brachytherapy as a modality for delivering the boost appeared to decrease over time [30]. This trend will likely be reinforced by the modern ways of delivering highly conformal external beam 3D radiotherapy and IMRT, that allow further technical improvements such as the simultaneous integrated boost technique [31], [32]. Acknowledgements This publication was supported by Grant Nos. 5R10-CA11488-11–5U10-CA011488-38 from the National Cancer Institute (Bethesda, MD, USA) and by a donation from the “KWF Kankerbestrijding” (Netherlands Cancer League) through the EORTC Charitable trust. Its content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute. 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a Department of Radiation Oncology, Dr. Bernard Verbeeten Instituut, Tilburg, The Netherlands b EORTC Head Quarters, Brussels, Belgium c Department of Radiation Oncology, Centre Georges-François Leclerc, Dijon, France d Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium e Department of Radiation Oncology, Institute Curie, Paris, France f Department of Radiation Oncology, Rambam Medical Centre, Haifa, Israel g Department of Radiation Oncology, University Medical Centre, Leiden, The Netherlands h Department of Radiation Oncology, University Medical Centre, Nijmegen, The Netherlands i Department of Radiation Oncology, University Medical Centre, Lausanne, Switzerland j Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands  Corresponding author. Department of Radiation Oncology, Dr. Bernard Verbeeten Instituut, P.O. Box 90120, 5000 LA Tilburg, The Netherlands.
PII: S0167-8140(08)00376-9 doi:10.1016/j.radonc.2008.07.011 © 2008 Elsevier Ireland Ltd. All rights reserved. | |
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