1 Institut Gustave-Roussy, Villejuif, France; 2 Instituto de Radiomedicina, Santiago, Chile; 3 Institut National de la Santé et de la Recherche Médicale, XU 521, Villejuif, France
Received 1 April 2003; revised 27 May 2003; accepted 7 August 2003
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Abstract |
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A randomised trial was conducted comparing wide lumpectomy and breast irradiation with modified radical mastectomy. As the follow-up was long (mean duration 22 years), we analysed the variation in the effect of treatment over time.
Patients and methods:
The trial included 179 patients with a breast cancer measuring 2 cm at macroscopic examination. Eighty-eight patients had breast-conserving surgery and radiotherapy, and 91 underwent mastectomy. All patients had axillary dissection. The analyses were based on Cox models with time-dependent treatment effects.
Results:
The effect of treatment on death or metastasis did not vary with time. The risk of local recurrence was lower during the first 5 years for the breast-conserving surgery group as compared with the mastectomy group, but higher after 5 years (P = 104 for a different treatment effect over time). Similar results were found in a database including 1847 patients with small breast tumours at diagnosis. In this analysis, late breast recurrences were also more frequent in the breast-conserving surgery group and this treatment effect was greater among younger patients (40 years at the time of diagnosis).
Conclusions:
Late breast recurrences were more frequently observed in younger patients treated with breast-conserving treatment compared with those submitted to mastectomy. These results require confirmation in other randomised studies so that younger patients with early breast cancer can receive adequate counselling and so that a more stringent long-term follow-up policy can be adopted when breast-conserving treatment is planned.
Key words: breast-conserving surgery, early breast cancer, late local recurrence, randomised trial, total mastectomy
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Introduction |
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We previously reported 15-year results of one of these randomised trials [5] and we report now the 22-year results focusing on the time-dependent variation in the effect of treatments on different events.
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Patients and methods |
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Axillary dissection of level I nodes was carried out in all patients, followed by frozen-section examination of at least seven lymph nodes. Complete axillary dissection was done only in patients presenting at least one involved axillary lymph node.
All patients included in the BCS group received breast irradiation at a dose of 45 Gy in 18 fractions over 30 days using cobalt 60 photon beams. A boost dose of 15 Gy in six fractions was delivered to the tumour bed.
Patients with histologically proven negative axillary lymph nodes did not receive nodal irradiation. Patients with positive axillary nodes (N+) were offered random allocation to postoperative nodal irradiation versus no further treatment. When lymph node radiotherapy was carried out, a total dose of 45 Gy in 18 fractions was delivered to the axilla, and the supraclavicular and internal mammary chain areas. In total, 25 patients with N+ disease out of 58 did not receive lymph node irradiation (11 in the BCS group and 14 in the mastectomy group). Beam arrangements have been described elsewhere [13]. No patient received adjuvant chemo- or hormonal therapy. After completion of treatment, patients were seen every 4 months for the first 2 years, then every 6 months up to 5 years, and yearly afterwards, with a yearly mammogram and a clinical examination at each visit. Complementary examinations were requested in cases of clinical symptoms or signs.
The histopathological diagnosis of breast recurrences was reviewed and compared with that of the initial tumour taking into account: cytological, morphological/architectural and stromal patterns, histological grade and immunohistochemical staining (hormonal receptors, c-ErbB2, E-cadherin and CA 15-3). The majority of these parameters had to be similar for a given lesion to be declared a true recurrence.
To verify the validity of the results obtained for local recurrence and contralateral breast cancer (CBC), we also analysed 1847 patients (632 had a BCS and 1215 a total mastectomy) abstracted from the Institut Gustave-Roussy (IGR) 19541983 database but not included in this trial. All these patients presented with a macroscopic tumour measuring 2.5 cm and received the same irradiation protocol as the patients in the trial.
Statistical methods
The trial was designed as an equivalence trial to test the following null hypothesis of no equivalence, namely that the 5-year overall survival rate would be <85% in the BCS group and attain 95% in the mastectomy group. With a one-sided alpha risk of 0.10 and a power of 0.90, 165 patients were required.
Randomisation lists were generated by blocks of six patients. The resulting treatment allocations were placed in numbered and sealed envelopes, which were opened by the pathologist when the patient was definitely eligible. The randomisation result was then communicated to the surgeon.
The primary end point was death and secondary end points were total tumour events. Multivariate Cox models [15] were used for long-term analyses in two steps: (i) We first tested whether the effect of treatment was constant over time for each type of event [16]: death, local recurrence (chest wall or breast), regional (lymph node) recurrence, distant metastasis, CBC and new primary malignancies (NPMs). (ii) When treatment effects were not constant over time, the time axis was split into two periods (before/after 5 years) to quantify these effects in each period [16]. Cox analyses were stratified on nodal status and nodal irradiation, and adjusted on age group (40, 4150, 5160, >61 years).
Local recurrence and CBC rates were also analysed by treatment group in patients from the IGR database with a Cox model adjusted on age groups, axillary node involvement, histological grade [17] and tumour size.
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Results |
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Variation in treatment effect with time
Table 1 details the variation in the treatment effect with time for each type of event. The treatment effect was not constant over time for local recurrence and CBC. The mean interval between randomisation and the occurrence of a local recurrence was six times longer in the BCS group than in the mastectomy group. For CBC the mean interval was twice as long as in the BCS group but there were no differences between groups in terms of other events.
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Comparison of the primary tumour and breast recurrence in the BCS group
Among the 14 breast recurrences, histological characteristics were not available for one patient. Among the other patients, 10 of 13 recurrences occurred in the same breast quadrant as the primary tumour. The histological features corresponded to those of the primary in nine out of 13 cases. Overall, the site and/or the histological features were akin to those of the primary in eight of 13 cases (62%). The interval between the primary treatment and the onset of the local recurrence was significantly different between concordant and divergent lesions (123 versus 211 months, respectively; P = 0.045, two-tailed MannWhitney test), indicating that early and late recurrences are probably different malignant entities.
Treatment of breast recurrences and survival after local recurrence
In spite of excess risk of late local recurrences in the BCS group, the risks of death and metastasis did not differ between the two treatment groups. Indeed, the overall survival rates after local recurrence were similar between the two groups of treatment. These rates at 5 and 10 years were 75% and 65% in the BCS group, and 78% and 67% in the mastectomy group.
Local recurrence and CBC rates in the IGR database
As the number of patients included in the randomised study was small, we examined the local recurrence and CBC rates in the described population of the IGR database. Results were similar (Figure 3) to those concerning patients in the trial (Figure 2). In this population, we further analysed the treatment effect according to age for local recurrence and CBC (Table 3). A major difference in local recurrence was observed between treatments (36% versus 12%, 15-year rates) in the younger patients (40 years), as shown in Figure 4. In this subgroup of patients, the risk of local recurrence after 5 years was 12-fold higher in the BCS group than in the mastectomy group (P = 106). This risk was only three-fold higher for the older patients (
41 years) and this difference was also highly significant (P = 106).
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Discussion |
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Van Dongen et al. [6], in a large randomised trial including patients with T1 and T2 tumours, showed a higher incidence of locoregional recurrence at 10 years in the BCS group (20%) than in the mastectomy group (12%). It could be contended that these results concerned patients with tumours >2 cm macroscopically. However, our own results indicate that the long-term effect on local recurrences also exists for smaller tumours.
If this long-term effect is real, it must be determined whether local recurrences are true recurrences of the primary or new ipsilateral breast cancers. Some arguments are in favour of the second possibility: (i) the local recurrence rate and the CBC rate were similar (Figure 2); (ii) the younger age at diagnosis of patients with a late local recurrence could indicate a radiation-induced carcinogenic effect; and (iii) the mean time between diagnosis of the primary and a breast recurrence was significantly longer for patients whose recurrence exhibited a different histology and/or was in a different quadrant as compared with the primary.
However, the other hypothesis is equally feasible: (i) most recurrences occurred in the same quadrant as the primary and they had corresponding histological features; (ii) the diagnosis of local recurrence may have simply been delayed in the BCS group. This second possibility is in accord with the lower incidence of local recurrence in this group during the first 10 years of follow-up.
Smith et al. [26] analysed a series of 1152 patients treated with BCS and radiotherapy and found 136 ipsilateral breast recurrences. According to the tumour location, histological subtype and flow cytometry findings, they classified ipsilateral recurrences as true recurrences or NPMs. The 15-year rate was 6.8% for true recurrences and 13.1% for NPMs. More interestingly, an increased incidence was only observed for the latter tumours after 10 years of follow-up. Our trial results are in accord with their findings.
More recently, two large randomised trials [11, 12] have reported long-term results, but the definitions of local recurrence and the methodology used are not comparable with ours. For instance, in the National Surgical Adjuvant Breast and Bowel Project trial [11], tumours in the ipsilateral breast after tumorectomy were not considered as recurrences when compared with the group of patients treated with total mastectomy.
Our results (Table 3 and Figure 4) confirm that a young age at the diagnosis of primary breast cancer is a strong prognostic factor for local recurrence in the BCS series and not in patients treated with total mastectomy [12, 19, 2629]. If these results are corroborated, younger patients should be informed of the higher risk of local recurrence when BCS is chosen. The present results do not show a deleterious effect in terms of overall survival or distant metastases; on the contrary, they rather favour the breast-conserving approach. However, recent studies have shown that an excess of local recurrences may subsequently increase the incidence of distant metastasis and eventually lead to a decrease in overall survival [22, 30, 31]. Knowledge of the long-term local results of BCS should not necessarily discourage specialists or patients from choosing this option. However, a major effort should be envisaged so that breast recurrence can be diagnosed early in these patients, through more regular long-term follow-up and probably more frequent recourse to new diagnostic tools such as magnetic resonance imaging and imaging-guided biopsies [32] when indicated by baseline clinical or imaging examinations.
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Acknowledgements |
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Footnotes |
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References |
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