1 Institut Gustave-Roussy (IGR), Villejuif; 3 Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France; 2 Instituto de Radiomedicina (IRAM), Vitacura, Santiago, Chile
Received 9 July 2001; revised 15 January 2002; accepted 11 February 2002
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Abstract |
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Analyses of predictive factors for local recurrences are important, as an increasing number of patients with early breast cancer opt for a breast-conserving procedure. This study investigates whether factors predictive of local recurrence differ between patients treated with conservative or radical surgery.
Patients and methods:
Two thousands and six patients with invasive breast carcinoma (25 mm) were included. Of these patients, 717 were treated conservatively (lumpectomy and breast irradiation) and 1289 were treated with total mastectomy. All patients had axillary dissection and received lymph node irradiation if axillary nodes were positive. Most patients did not receive adjuvant chemotherapy or additive hormonal treatments. The mean duration of follow-up was 20 years. The main end point was the total local recurrence rate. The risk factors of local recurrence were estimated by multivariate analyses and interaction tests were used for intergroup comparisons.
Results:
Statistically significant predictive factors for mastectomized patients were histological grade, extensive axillary node involvement (10 nodes or more), and inner quadrant tumors, which were of borderline significance. Young age, however, was not a prognostic indicator for local recurrence. The main statistically significant factor for patients treated with a conservative approach was young age (40 years). These younger patients had a five-fold increased risk of developing a breast recurrence compared with patients older than 60 years.
Conclusions:
Younger patients with early breast cancer treated with breast-conserving surgery should in particular be followed up at regular intervals so that any sign of local failure can be diagnosed early.
Key words: breast cancer, breast-conserving surgery, local recurrence, mastectomy, multivariate analysis, prognostic factors
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Introduction |
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To search for additional information on this subject, we compared the factors related to the risk of LR in patients treated with a different surgical approach, in a series of operable breast cancer that originated from the Institut Gustave-Roussy (IGR) database. To avoid biases related to tumor size, we limited the analysis to patients whose tumor was 25 mm.
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Patients and methods |
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Tumor size was determined during the perioperative macroscopic examination of the fresh tumorectomy specimen by direct measure of the greatest tumor diameter. This examination also permitted verification of, for patients to be treated with BCS, the presence of a minimum of 1 cm of macroscopically normal breast tissue surrounding the tumor, or to request, if necessary, an additional surgical excision. For the processing of axillary lymph nodes after tissue fixation, each lymph node identified during dissection was included in entirety in the macroscopic serial slices [43].
The series included 717 patients treated with BCS [452 with negative axillary nodes (N) and 265 with positive axillary nodes (N+)] and 1289 treated with total mastectomy (622 N, 667 N+). The mean duration of follow-up was 20 years (standard deviation 7 years) for survivors.
Treatment
For N patients, external megavoltage irradiation exclusively encompassed the breast in BCS cases and was omitted in total mastectomy cases regardless of the tumor site. For N+ patients, the irradiation fields encompassed the breast and/or chest wall, and locoregional (axillary, supraclavicular and internal mammary chain) lymph nodes. The radiation dose delivered was 45 Gy in 18 fractions and patients submitted to BCS systematically received a boost dose of 15 Gy in six fractions [44].
Patients with negative nodes did not receive systemic adjuvant treatment. For N+ patients, ovarian suppression was achieved with radiotherapy in 26% of cases, and chemotherapy or additive hormonal therapy were given in only 3% of patients.
Statistical methods
The main end point was the total local recurrence rate. LR was defined as any recurrence in the breast or chest wall, and the total number of LR was 211. The mean disease-free interval between initial surgery and recurrence was 6.8 years (SD 5.6 years).
We studied the relationship between the risk of LR and six clinical and histological covariates, i.e. age at diagnosis of the primary tumor, macroscopic tumor size, SBR grade, tumor location (inner quadrants compared with other sites), and the number of examined and involved axillary lymph nodes.
The risk of LR was estimated using the Cox proportional hazard model [45], and analysis began from the date of diagnosis of the primary tumor. Censoring began either on the date of a LR, or the date of the last medical follow-up or death for patients without a LR. Any other events such as metastases or a new primary were not censored.
First, we analyzed negative and positive axillary nodes separately because indications for radiotherapy differed according to the histological status of axillary nodes. Secondly, to determine to what extent the type of surgery or the lymph node status could modify the effect of other factors, or similarly to what extent the latter factors could modify the effect of the former factors, we used interaction tests for the total patient population [4648]. Interactive effects were assessed by the likelihood ratio tests used to compare the goodness of fit of the models with and without the interaction term [48]. The interaction tests were performed by introducing multiplicative terms for the factors of interest, i.e. lymph node involvement and surgical treatment groups.
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Results |
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Discussion |
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The cutoff at 40 years, used to define young age, took into account the number of patients available (248 in total, 12% of the total population). The increased risk of LR (P = 0.07) for patients treated with BCS was demonstrated to be of borderline significance according to the trend tests for N (Table 2) and N+ patients (Table 3). The possible lack of power in the statistical analysis of these subgroup analyses was confirmed by the highly significant trend test (P = 104) for the total number of BCS cases (717) as shown in Table 4. This effect of young age was totally different to that found in patients treated with mastectomy according to the test presented in Table 5, where both surgical approaches were compared directly (interaction test with a P value of 106).
The effect of young age on the risk of LR for patients treated with BCS has been recognized in most studies on prognostic factors [2, 6, 15, 18, 19, 61]. The recent study by Voogd et al. [17], conducted in a randomized population of 1772 patients (879 treated with BCS and 893 with mastectomy), corroborated this fact. Two differences should be pointed out between this analysis and our own. The first is that Voogd et al. used separate tests for each age group whereas we used a trend test for all age groups. This latter analysis allowed us to test the whole series and not make assumptions about an age cutoff value. Indeed, both studies clearly indicate that there is no obvious age cutoff, and that a young age is rather related to a continuous trend towards a higher risk of LR. This is clearly observed in Figure 1, where there is only a decreased effect of age after 50 years. This change in the trend could be related to the menopausal status. The second difference is that Voogd et al. did not directly compare patients treated with BCS with those treated with mastectomy (despite the fact that data on this specific treatment factor were randomized). In our study, we applied interaction tests to decrease the likelihood of biases related to the comparison of non-randomized data, which obviously attract criticism. The extremely low P value yielded by such a test in our series allows us to predict that similar results would have been obtained with the Danish-EORTC (European Organization for Research and Treatment of Cancer) data.
Few series have taken tumor location into account [5, 62, 63]. We included this factor as it was registered systematically in the IGR database. As shown in Tables 34, inner quadrant tumors were found to exhibit a trend towards a higher risk of LR. There was no difference between the surgical approaches, as shown in Table 5, using a non-significant interaction test (P = 0.87). Fowble et al. and Lohrisch et al. [62, 63] found no relationship between tumor location and local recurrence in their series.
Macroscopic tumor size (pT) was also taken into account. Due to the initial patient selection, variation in tumor sizes was very limited. This factor was not predictive of the risk of LR for lesions measuring up to 25 mm in the BCS group. The effect of larger tumors (1625 mm) in the mastectomy group was of borderline significance and it should probably be rejected, since the P value of the interaction test was also low (P = 0.06). Furthermore, in larger series of mastectomized patients in the same IGR database, which included all tumor sizes, we found that tumor size had no effect on local recurrence [64]. However, for patients treated with BCS it would be of interest to continue investigations into the potential effect of tumor size. These studies should be conducted in randomized trials evaluating BCS and including patients with a tumor >3 cm [30, 65]. Incidentally, the report by Voogd et al. [17] showed a non-significant trend towards a higher risk of LR for patients with tumors >1 cm in diameter.
As shown in Table 4, SBR grade was a predictive factor for LR in mastectomized patients, as we and others have reported elsewhere [64, 66]. However, there is no demonstrated difference between BCS and mastectomy groups as shown in Table 5, where the interaction test was not significant (P = 0.10). In the trials reported by Voogd et al. [17], histological grade was of borderline significance in the BCS group (P = 0.07) when other factors such as vascular invasion were taken into account. A general effect may exist but very large numbers would be required to attain statistical significance.
The number of axillary lymph nodes examined was not predictive of LR in any of the analyses, and its prognostic value should be rejected in patients with small tumors in whom the risk of having positive axillary nodes was low.
The number of positive axillary nodes was not a predictive factor for LR in the BCS group with N+ patients, but it was a highly significant factor for mastectomized patients (Table 3; P = 0.0006). This effect has been reported previously [64]. However, this effect disappeared when N+ patients were pooled with N patients (Table 4), and only extensive axillary involvement (10 or more nodes) maintained a prognostic value as seen in Tables 4 and 5. It is noteworthy that all N+ patients received loco-regional radiotherapy and this treatment could have canceled the prognostic effect of the number of axillary nodes involved. A similar effect was described in the report by Voogd et al. [17].
Other factors such as extensive intraductal carcinoma [7, 2122] and surgical margins [8, 11, 2328] were not analyzed as they were not systematically coded in the database. However, the treatment policy at the IGR was to perform total mastectomy when the first factor was present and to request adequate surgical margins, i.e. at least 1 cm of macroscopically normal breast tissue surrounding the tumor when BCS was performed.
In summary, between the BCS and the mastectomy groups, the overriding differential effect predicting the risk of LR was young age. Conservatively treated patients aged 40 years or younger had a five-fold greater risk of LR compared with patients older than 60 years of age who had a baseline risk of LR of 6% at 10 years. This effect was not observed among mastectomized patients. Young age has also been described as a significant prognostic factor for overall survival [6771]. That local recurrence may have an impact on distant metastasis and overall survival is also becoming widely recognized [35, 3740, 7278]. However, as systemic treatments also have a positive impact on local control [79, 80] it can be hypothesized that the current indications for these treatments in intermediate- and high-risk patients could lower the effect of age on tumor recurrence, as observed in the present series. It may prove increasingly important to analyze the long-term results (20 years or more) of all randomized trials comparing systemic treatment with no systemic treatment in patients having undergone BCS. At the present time and given the consistency of the results yielded by different studies on prognostic factors, surgeons and oncologists should be aware of the increased risk of local recurrence in younger patients with early breast cancer treated with BCS. In particular, these patients should be followed up on a regular basis for several years so that any sign of local failure can be diagnosed early.
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Acknowledgements |
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Footnotes |
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