Annals of Oncology Advance Access originally published online on December 5, 2005
Annals of Oncology 2006 17(3):401-408; doi:10.1093/annonc/mdj080
© 2005 European Society for Medical Oncology
Long-term follow-up of a randomised trial designed to determine the need for irradiation following conservative surgery for the treatment of invasive breast cancer
1 Combined Breast Clinic, St George's Hospital, Blackshaw Road, London; 2 Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, DuCane Road, London; 3 CR(UK) Trials, Institute of Cancer Studies, Birmingham, UK
* Correspondence to: Mr J.-C. Gazet, 48 Wayneflete Tower Avenue, Esher Place, Esher, Surrey KT10 8QG, UK. Tel/Fax: +44-(0)1372-463-235; E-mail: jcgazet{at}aol.com
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Abstract |
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Four hundred consecutive patients aged under 70 years diagnosed with a clinical T1 or T2 breast cancer were randomised to receive post-operative radiotherapy (n = 208) or not (n = 192), and monitored to record all local recurrences, distant recurrences and deaths for up to 20 years (median 13.7 years). All patients were treated by wide local excision and adjuvant therapy [estrogen receptor (ER) positive: tamoxifen; ER negative: CMF chemotherapy]. Kaplan–Meier and log-rank test methods were used to estimate and compare survival and recurrence. The 20-year Kaplan–Meier rates for local breast recurrence were 28.6% [95% confidence interval (CI) 19.6% to 37.6%] for radiotherapy and 49.8% (95% CI 40.8% to 58.9%). There was no significant difference between the two groups with regard to disease-free or overall survival. The hazard ratio for death among women who received radiation, as compared with those that did not, was 0.91 (95% CI 0.64–1.28; P = 0.59). Therefore, post-operative radiotherapy produced a clear-cut reduction in locoregional recurrence 0.45 (0.31–0.64; P = 0.0001), but did not influence the incidence of distant metastases or time of death. However, of the 119 patients who had a local recurrence, 51 (42.8%) had a distant recurrence, whereas of the 281 without local recurrence only 59 (21%) ever had a distant recurrence. A Cox's regression analysis with local recurrence as a time-dependent variable showed a risk ratio of 5.28 (P < 0.0001). This strong relationship is dependent on the intensity of post-treatment follow-up and investigation.
Key words: breast cancer trial, radiotherapy, conservative surgery, chemoendocrine therapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsReferences |
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In 1978, in a review on the management of early breast cancer, Hughes and Forbes [1
] outlined the place of radiotherapy and cytotoxic chemotherapy. They noted that radiotherapy had been effective in reducing and delaying local recurrence after either simple mastectomy [2] or radical mastectomy [3]. However, two controlled randomised trials [4, 5] showed no survival advantage. In contrast, adjuvant chemotherapy showed an advantage in terms of reduced local recurrence in premenopausal women [5, 6], and trials at this time were also reporting an advantage in overall survival. There was considerable doubt as to the place of post-operative radiotherapy in the management of early breast cancer treated by wide local excision and appropriate adjuvant therapy. In 1981 we felt that wide local excision was an acceptable alternative surgical treatment for early breast cancer (T1 and T2). Therefore, this trial was set up to investigate the role of post-operative radiotherapy in patients with early breast cancer (T1 and T2) treated by wide local excision and appropriate adjuvant therapy, based on the estrogen receptor (ER) status of the primary tumour.
Since this time several units have designed studies to assess the value of radiotherapy in this group of patients [7–13]. These trials have recently been summarised. The conclusion was that post-operative radiotherapy reduced the risk of local recurrence but had no effect on overall survival [14]. We felt that analysis should be carried out at a 20-year time point, since other trials of radiation following breast-conserving surgery or not have tended to show effects on survival at later time periods [15]. In designing this trial, we decided to ensure that all patients received what was considered to be the optimal systemic therapy at this time, since several studies have highlighted the importance of systemic therapy in delaying local recurrence and improving overall survival [5].
Finally, we felt that this trial should be confined to one unit only to obviate the problems of multicentre recruitment.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsReferences |
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Between 1981 and 1990, 400 patients with T1 and T2 N0–N1, M0 invasive breast cancer seen in one unit agreed to enter the trial after giving informed consent. The trial had been approved by the St George's Hospital ethics review committee. The diagnosis was confirmed by mammography and fine needle aspiration cytology. No patient had evidence of metastases on standard screening [16
], which included chest radiography, bone scan, liver ultrasound, full blood count and liver function tests. We excluded patients with multifocal disease or who were over 70 years of age, patients with significant cardiac or renal impairment, and those with a previous history of cancer. In this single-centre study, patients were treated by wide local excision and adjuvant therapy dependent on ER status. A tumour was defined as ER positive if >30% of malignant cells in representative sections stained positive with ER-ICA Abbott [17] or if it contained >10 fmol ER/mg cytosol protein as detected by the dextran-coated charcoal method [18]. On the basis of ER status, all patients who were ER positive received tamoxifen 20 mg daily for 2 years and all who were ER negative received six courses of CMF (cyclophosphamide 100 mg orally daily, days 1–14; methotrexate 40 mg/m2 on days 1 and 8; and 5-fluorouracil 750 mg/m2 days 1 and 8 by bolus injection). Patients in each group (ER positive or ER negative tumours) were separately randomised from random numbers tables, to have or not post-operative radiotherapy irrespective of nodal status, pre- or postmenopausal status or T-stage.
Radiotherapy was given post-operatively as soon as possible and was followed by the appropriate chemo-endocrine therapy.
Radiation treatment was given to the breast to a maximum tumour dose of 54 Gy, given in 27 daily fractions of 2 Gy through parallel opposed glancing wedged fields using a 6 MEV linear accelerator. In axillary node positive patients, the axilla received a tumour dose of 50 Gy mid-plane dose, and the supraclavicular area received a tumour dose of 50 Gy at 2–5 cm depth. These areas were treated using an anterior field covering the axilla and supraclavicular region, with lead shielding to the upper humerus and shoulder joint and to the lung lying between the upper border of the glancing fields and below the clavicle. A small posterior axillary field was used to bring the mid-plane axillary dose to 50 Gy when the supraclavicular field reach 50 Gy. Supplementary axillary dose was divided into 25 daily fractions.
All patients received a boost to the tumour site of 10 Gy given in five daily fractions of 2 Gy using either a 300 KV X-ray machine or occasionally 10–14 MEV electrons. There was no deliberate policy of treating the internal mammary nodal chain except when the primary tumour was situated in the medial half of the breast, and this excluded central tumours. Eighty patients had a tumour in the medial half of the breast: 39 were in the radiation group and received radiation to the internal mammary chain.
Wide local exicison was defined as an excision with a gross margin of clearance of at least 1 cm. All tumours were examined by frozen section at the time of surgery to confirm the diagnosis made by cytology (fine needle aspiration) and that the excision was wide and complete. Confirmation of this was made in all cases by examining six representative surfaces by frozen section and the clearance reported in millimetres from the ‘inked’ margin. Furthermore, all specimens were assessed on paraffin section to confirm that all margins were clear.
Through a separate axillary incision a level I axillary dissection was performed in all patients with an analysis of an average of 10 nodes.
Patients were followed up 3 monthly for 2 years, 6 monthly for 3 years and annually thereafter. Apart from routine follow-up and investigations as required, all patients were routinely screened for metastatic disease at 2 and 5 years post-surgery [16].The primary end points were evidence of loco-regional recurrence or distant metastases. The censoring point was the date last seen or date of death.
All patients were fully informed of the objects of the trial and the implications of randomisation. Written consent was obtained in every case according to the Helsinki agreement.
Standard Kaplan–Meier test methods [19] were used for estimation of survival and recurrence rates and comparisons made using the log-rank test [20]. Odds of death and recurrence and the tests for heterogeneity of treatment effects between subgroups used methods described by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) [21]. Cox proportional hazards modelling was used to investigate the risk of distant recurrence before and after local recurrence. This was done by modelling distant recurrence in the presence of a time-dependent variable taking two values for ‘before’ and ‘after’ local recurrence. SAS statistical software was used.
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results |
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The median follow-up for surviving patients is now 13.7 years (range 13–22). The two groups, post-operative radiotherapy or not, were well matched according to age, menopausal status, T-stage, N-stage and estrogen sensitive tumours (Table 1). One hundred and ninety-five patients were premenopausal. One hundred and forty-seven patients (37%) had small (T1) tumours and 100 patients had histologically involved axillary nodes. Two hundred and seventy-eight patients had ER-positive tumours.
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All patients completed their their allotted treatment and follow-up was complete.
recurrence in the ipsilateral breast after lumpectomy
Postoperative radiotherapy reduced the risk of local breast recurrence significantly (P = 0.0001) in all patients (Figure 1). The 20-year Kaplan–Meier rates for local breast recurrence were 28.6% [95% confidence interval (CI) 19.6% to 37.6%] for radiotherapy and 49.8% (95% CI 40.8% to 58.9%) for no radiotherapy. The benefit of radiation was independent of node and ER status, and was not related to T-stage. The odds ratio plots this graphically (Figure 2).
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distant disease-free survival
One hundred and ten (27.5%) patients had developed distant metastases but this appeared unrelated as to whether they had received radiotherapy (Figure 3). The 20-year Kaplan–Meier rates for development of metastases were 33.8% (95% CI 25.1% to 42.5%) for radiotherapy and 32.2% (95% CI 24.7% to 39.7%) for no radiotherapy. The hazard ratio for distant metastases among women who underwent surgery alone as compared with those who had both surgery and radiotherapy was 0.91 (95% CI 0.64–1.33; P = 0.63) (Figure 4).
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A significant interaction between menopausal status and radiotherapy effect exists, suggesting that the effect of radiotherapy is greater in postmenopausal women (P = 0.02). This may be a chance finding (Figure 5).
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overall survival
There was no significant difference in overall survival between the treatment groups (P = 0.59) (Figure 6). Twenty-three patients died of non-breast cancer causes, 13 in the irradiated group and 10 in non-irradiated group. The cause of death was not known in 12 patients (six in each group). An analysis of breast cancer deaths did not appear to show any effect of radiation (P = 0.44) (Figure 7). We again examined the data to see whether there was any effect in subsets of patients in terms of node status, ER status and T-stage, as well as menopausal status, but again no benefit in any of these groups was seen (Figure 5). At 20 years, overall survival was 60.5% [standard error (SE) 4.7%] among the women treated with wide excision and radiation compared with 56.7% (SE 6.1%) among the women who had wide local excision alone.
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There was no significant difference between the two groups with regard to disease-free or overall survival. The hazard ratio for death among women who received radiation as compared with those who did not was 0.91 (95% CI 0.64–1.28; P = 0.59). Therefore, post-operative radiotherapy produced a clear-cut reduction in locoregional recurrence (0.45; range 0.31–0.64; P = 0.0001), but did not influence the incidence of distant metastases or time of death.
There was a strong association of local recurrence in the breast with distant metastases. Of the 119 patients who had a local recurrence, 51 (42.8%) had a distant recurrence (nine at the same time and 42 later), whereas of the 281 without local recurrence only 59 (21%) ever had a distant recurrence. This suggests that patients who had a local recurrence are more likely to develop distant metastases than those who do not have a local recurrence.
To test this statistically a Cox's regression analysis was performed with local recurrence as a time-dependent variable. In a conservative analysis, i.e. assuming that where local and distant recurrences were found on the same date, the distant recurrence was first, the risk ratio was 5.28 with a P value of >0.0001.
If instead, where local and distant recurrences were found on the same date, the distant recurrence is not assumed to have been first, the effect of local recurrence is even higher, at 7.61. The strong apparent relationship should be interpreted in the light of the investigations used. Thus, as all patients were intensively investigated for metastatic disease, at 2 and 5 years post-surgery and then, as indicated, the observation becomes of greater significance (Figure 8).
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discussion |
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This trial clearly shows that post-operative radiotherapy significantly reduces the incidence of local recurrence in early invasive breast cancer (T1, T2 tumours <5 cm, N0–N1) treated by breast-conserving surgery over long-term follow-up. This occurred in both node-positive and node-negative patients without apparently influencing the time to distant metastases or death. This requires explanation.
In a study of this nature, uniformity of both surgery and radiotherapy is essential. This is of great importance since local breast recurrence has been shown to be more common in patients where there is disease at the resection margin, irrespective of nodal, menopausal or ER status [22, 23].
All patients received the optimal chemo-endocrine therapy current at the time of the trial. Latterly in 2004, the EBCTCG have shown in their overview that tamoxifen given over 5 years is the treatment of choice for ER-positive patients. Although to some extent CMF has been replaced by combinations containing anthracyclines, this treatment is still considered adequate in most centres; recent studies by our group have confirmed this [24].
It is accepted that current thought suggests that all patients should receive post-surgical chemoendocrine therapy.
In breast-conserving operations for early breast cancer, there is currently no agreement as to whether wide local excision or quadrantectomy is the preferred surgical procedure for unicentric invasive tumours. We used frozen sections to ensure the adequacy of excision at the time of surgery, thus obviating the need for a second operation. The current acceptable clearance is at least 1 cm. Clearly, breast-conserving surgery can never be satisfactory for multicentric tumours; conversely it is ideal for localised screen-detected tumours.
There is extensive evidence supporting the use of locoregional radiotherapy in preventing local recurrence after wide local excision, segmental resection or mastectomy [25–27]. Local control may be enhanced if a boost is given to the excision site by external beam therapy or brachytherapy [28]. However, adjuvant radiotherapy may result in an increased incidence of second tumours and heart disease among patients with the best prognosis [15, 29]. Yet Palmer and Ribeiro [30] have reported a 34-year follow up of 1461 patients entered into a trial of immediate or delayed post-mastectomy radiotherapy without evidence of any harmful effect. There is now good evidence that modern irradiation techniques using megavoltage therapy reduce the dose of radiation to the heart [31]. Furthermore, fractionation sequencing of radiotherapy and adjuvant therapy may be important as an optimum has yet to be determined [32].
Only seven multicentric trials of early breast cancer treatment based on breast-conserving surgery with post-operative radiotherapy or not have been reported in full or abstract form. All shared a substantial reduction in local recurrence where radiation was given. However, none of the trials are comparable and all have, in our opinion, significant differences. Four trials resticted inclusion to patients with tumours <4 cm in diameter [7, 9, 11, 13], one to tumours <3 cm [12], another to tumours <2.5 cm [10] and the last to tumours <2 cm [8]. In one, where positive margins had been found, the treatment changed to a mastectomy but the patient was still included in the randomisation on the principle of ‘intention-to-treat’ [11]. One trial from 11 centres excluded premenopausal, node-positive patients [13], with four others including only node-negative patients [7–9, 12]. These node-positive patients, in our experience, form a significant group and in the premenopausal state have a particularly bad prognosis. Two trials gave no adjuvant therapy, and a further two, only to patients proven to be node positive. The radiotherapy was generally similar, though fields were not always clearly defined, with no clear indication of whether the internal mammary chain of nodes were treated routinely or only for medially placed tumours. Finally it was difficult to establish the mortality rate in all the trials. Two trials included fewer patients than this trial, two had the same number and two trials had 736 and 837 patients, respectively. Only one trial recruited more than 1000 patients.
However, considering these seven trials with the current one, it is clear that tumour size plays a part as the incidence of locoregional recurrence increases in relation to the size of the primary tumour irrespective of other factors.
The advantage of this trial is the homogenicity of the material achieved by careful selection and the treatment of the patients within one single institution.
In the overview of the favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer, the EBCTCG [15] identified 45 trials, analysing 40, of which only 10 were confined to breast-conserving surgery.
Radiotherapy improved the survival from 48.6% in controls to 53.4% in radiotherapy-treated patients at 20 years follow-up. This was due to a fall in the number of deaths from breast cancer in the radiotherapy treated group. However, mortality from vascular disease was significantly increased by post-operative radiotherapy when all deaths were considered.
It must be noted that the percentage of deaths in patients allocated to radiotherapy where the cause of death was not known was 29.2% and in the adjusted controls 31.4%. The analysis did provide a fairly reliable assessment of the average effects on survival in those allocated radiotherapy with a moderate but statistically beneficial effect during the first decade or two, and a moderate hazard that grew progressively larger with longer follow-up.
The important question that has to be answered is: does local recurrence affect the rate of distant metastases and survival in patients with early-stage breast cancer treated by breast-conserving surgery? Our results would suggest that it does, as the incidence of distant metastases at any time is double in the patients who had a local recurrence compared with those who did not. Local recurrence is a marker of distant recurrence and post-operative radiotherapy does not have much effect on the incidence of distant metastases [25].
Vicini et al. [33] in posing this question have attempted to answer it by examining a cohort of patients treated by conservative surgery and radiotherapy. Their local recurrence rate at 12 years follow-up was 11% in 1169 patients. One hundred and forty-one died, of which 110 (9%) were related to breast cancer. Of the patients without local recurrence, 13% developed distant metastases; with an overall survival of 81% (cause-specific 88%); whereas of those with local recurrence, 33% developed distant metastases with an overall survival of 71% (cause-specific 69%). This 10% difference was not related to non-cancer deaths (vascular causes), as all patients had had radiotherapy. The mean time to development of distant metastases was earlier in those who did not develop local recurrence (3.8 years) compared with those who did (4.8 years). This agrees with our finding that the incidence of distant metastases increases rapidly to 20% at 5 years with minimal increase at 10 years in those who never had a local recurrence (Figure 8), irrespective of whether the patients had radiotherapy or not.
The prevention of local recurrence by adequate surgery and radiotherapy is paramount, but it will not prevent the development of distant disease in patients with co-existent micrometastases. However, in patients who do not have occult micrometastases, radiotherapy will reduce the incidence of local recurrence at any time in patients having breast-conserving surgery.
The paradox of why the prevention of local recurrence by post-operative radiotherapy in breast-conserving surgery does not influence either the incidence of distant metastases or survival remains perplexing. However, this problem could be explained if one accepts the suggestion that the incidence of unquantifiable occult micrometastases are present randomly in patients presenting with early breast cancer.
Certainly, there is enough evidence from long-term follow-up studies [34, 35] to show that the detection of micrometastases in bone marrow is associated with a higher risk of relapse, particularly within 5 years. Furthermore, the prevalence of micrometastases increases to 19% in patients with locally recurrent disease. Adjuvant therapy did not affect the disease-free interval, although the prognosis was worse for patients who had micrometastases whether or not they had the conventional adjuvant therapy current at that time [35].
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Our results support a role for breast irradiation in patients who have had conservative surgery for breast cancer. Radiation prevents the need for further surgery, which in most cases of local recurrence would be a mastectomy. It prevents the psychological effects of local recurrence, which can be devastating for patients. It may not be necessary in small tumours or unifocal screen-detected lesions [36
]. The consensus must be, at present, that in breast-conserving surgery the advantages of carefully controlled fields of post-operative radiation in controlling locoregional recurrence is such that it outweights its disadvantages, and it should be considered in every case. The corollary is that surgery must be shown to be adequate with clear margins of resection proven by histological examination. However, local control of breast cancer does not guarantee that the patient will neither develop distant metastases nor die from the disease.
It would seem that the chemo-endocrine adjuvant therapy given during this trial had little effect in reducing the incidence of distant metastases.
Long-term trials of intensive and prolonged chemo-endocrine therapy may suggest a solution to the problems that have been highlighted in this trial.
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Notes |
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Deceased. 
Received for publication April 14, 2005. Revision received October 7, 2005. Accepted for publication October 14, 2005.
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