1 Division of Senology, 2 Division of Radiotherapy and 12 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan; 3 Division of Surgery, Pascale Institute of Cancer, Naples; 4 Division of Surgery, University of Florence, Florence; 5 Division of Surgery, Ospedale Maggiore, Parma; 6 Division of Surgery, Ospedale Molinette, Turin; 7 Division of Surgery, University of Perugia, Perugia; 8 Division of Surgery, Ospedale Oncologico Maurizio Ascoli, Palermo; 9 Divison of Surgery II, Ospedale di Lecco, Lecco; 10 Istituto Patologia ChirurgicaGemelli, and Università Cattolica Sacro Cuore, Rome; 11 Division Surgery C, Policlinico GB Rossi, Verona, Italy
* Correspondence to: Professor U. Veronesi, Istituto Europeo di Oncologia, Via G. Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57 489-221; Fax: +39-02-57 489-210; Email: umberto.veronesi{at}ieo.it
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Abstract |
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Patients and methods: From 1995 to 1998, 435 patients over 45 years old with breast cancer up to 1.2 cm and no palpable axillary nodes were randomized 214 to breast conservation without axillary treatment and 221 to breast conservation plus axillary RT.
Results: After a median follow-up of 63 months, overt axillary metastases were fewer than expected: three cases in the no axillary treatment group (1.5%) and one in the RT group (0.5%). Expected cases were 43 in the no axillary treatment group and 10 in the RT group. Rates of distant metastases and local failures were low, and 5-year disease free survival was 96.0% (95% confidence interval, 94.1%97.9%) without significant differences between the two arms.
Conclusions: This study suggests that occult axillary metastases might never become clinically overt and axillary dissection might be avoided in patients with small carcinomas and a clinically negative axilla. Axillary RT seems to protect the patients from axillary recurrence almost completely.
Key words: axillary radiotherapy, breast cancer, lymph nodes, metastases, randomized trial
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Introduction |
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The possibility that occult axillary metastases may never become overt poses the problem of whether patients with very small carcinoma should be offered the option of avoiding axillary dissection. The sentinel node biopsy procedure, although very useful for detecting pathologically positive cases, might become unnecessary in some subgroups of patients with very early breast carcinoma.
An alternative to surgery is radiotherapy (RT) to the axilla. RT may destroy occult cancer foci in the axilla, as in other areas, without major side-effects [12].
To explore the natural history of occult node metastases and the possible role of axillary RT in early breast cancer, the Italian Oncological Senology Group (GrISO) initiated a randomized trial in 1995. Patients with tumors up to 1.2 cm received conservative breast surgery without axillary dissection or sentinel node biopsy, and were then randomized either to axillary RT or to no treatment to the axilla. The 1.2 cm maximum diameter was chosen as it represents 50% of the volume of a tumor with a diameter of 2.0 cm. The primary end point was the rate of overt axillary metastases appearing in the two groups in the follow-up. The secondary end point was disease-free survival.
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Patients and methods |
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Surgery
Wide resection or quadrantectomy (12 cm margin of normal tissue) of the primary carcinoma was the standard surgical approach [13]. Quadrantectomy for tumors in the upper outer quadrant were carried out without removal of any axillary node. Where lesions were non-palpable, the removed specimen was X-rayed to check that the tumor had been removed completely. The size of the lesion was determined macroscopically in the operating theater. The final histological size measurement was concordant in most cases. However, in 9.2% of cases (20 in each group), size was in excess of 1.2 cm.
Radiotherapy
Breast treatment (all patients). X-Ray photons from a 6 MV linear accelerator were used to produce two opposed tangential fields, non-parallel to avoid posterior beam divergence and minimize lung and heart (for left breast) irradiation. Central lung distance never exceeded 2 cm. The fields were designed to avoid irradiation of the axillary nodes. Medial and lateral wedges were used as compensators to ensure that dose inhomogeneity was no greater than 5%. The 100% tumor dose (50 Gy in 25 fractions of 2 Gy each) was specified at the isocenter (ICRU point). Correction factors for lung were also used to calculate the dose distribution. An additional boost with 615 MeV electrons (10 Gy in five fractions of 2 Gy each) was given to all patients, limiting the field to the tumor bed.
Axilla (axillary RT patients only). The axillary region was irradiated with two parallel (non-divergent) opposed fields (antero-posterior postero-anterior). The limits of the irradiation fields were: the upper border was the upper margin of the clavicle; the lateral border was the anterior axillary fold; the medial border was the margin of the vertebral bodies; and the inferior border was 0.5 cm from the upper limit of the tangential breast fields. The total dose, given with a 6 MV linear accelerator, was 50 Gy in 25 fractions of 2 Gy each. The isocenter point was at the midplane or slightly anterior. The shoulder joint was properly shielded.
Randomization
Randomization was centralized. Starting in February 1995, patients were assigned either to no axillary RT (no RT group) or to axillary RT (the RT group) by contacting the Division of Epidemiology, European Institute of Oncology. The trial closed for patient entry at the end of July 1998. One hundred and seventy-one patients from Milan were randomized; 88 from Naples; 45 from Florence; 32 from Parma; 29 from Turin; 25 from Perugia; and 45 from other Italian centers. Table 1 shows that the two groups did not differ in main characteristics.
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Statistical evaluation
The primary end point of the study was the cumulative number of patients in whom axillary metastases appeared during follow-up. On the assumption that radiotherapy will destroy occult cancer cells in the axilla in 80% of cases, at least 300 patients (150 in each arm) followed for 8 years would be expected to show a statistically significant reduction in axillary recurrences from an assumed 20% in the control arm to 4% in the axillary RT arm. With an axillary involvement rate of 20%, we expected that 30 of the 150 patients in the no axillary treatment group, and six of the patients in the axillary RT group would develop axillary metastases.
A secondary end point was disease-free survival, defined as absence of any event (specifically axillary metastases, local recurrence, ipsilateral carcinoma or distant metastasis) considered related to the primary cancer, but excluding contralateral breast cancer and any other cancer. Survival estimates were calculated by the KaplanMeier method and compared by the log rank test [14]. Patients with contralateral breast cancer and patients with non-breast cancer related events were censored at the time of the event. All statistical tests were two-sided.
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Results |
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During a median follow-up of 63 months, four patients developed axillary metastases: three in the no RT group, one in the RT group; among the three patients in the no-RT group with axillary relapse during follow-up, the final histology gave the following results: 2/19 positive nodes in one and 15/16 positive nodes in the second one. The third patient developed overt clinical axillary metastases and died before receiving axillary dissection, due to a severe pancytopenia. The patient in the RT group had 2/15 positive nodes. The three patients received complete axillary dissection and one of them (RT group) developed distant metastases. Two patients (one in each group) developed breast cancer recurrence (i.e. near the tumor bed) and three patients developed a second ipsilateral breast cancer (i.e. in other breast quadrants), all in the RT group. Eleven patients developed distant metastases as first event: eight in the no RT group, and three in the RT group. Of these 20 breast cancer-related events, 13 developed in (257) women operated before age 60 (eight in the no RT group and five in the RT group) and seven developed in (178) women operated after age 60 (four in the no RT group and three in the RT group). The five women who developed local recurrence or second ipsilateral breast cancer were age 55 years or less when operated on.
Eleven patients developed contralateral breast cancer (seven in the no RT group and four in the RT group) whereas eight patients developed other primary tumors, four in the no RT group (endometrial, ovary, colon, and brain) and four in the RT group (thyroid, stomach, squamous cell of the nose and bladder carcinoma).
There were seven deaths due to breast cancer, five in the no RT group and two in the RT group. Seven other patients died of other causes, all in the no RT group (Table 3): one patient died after the diagnosis of axillary metastases (no RT group) due to pancytopenia during chemotherapy. Two patients died from heart disease (myocardial infarction and acute heart failure), two other patients died from other primary tumors (colon cancer and glioblastoma of the brain). Two patients died from liver failure due to cirrhosis. The 5 year disease free survival was 96.0% [95% confidence interval (CI), 94.1%97.9%] with no significant difference in the two groups: 95.1% (95% CI, 92.2%98.1%) in the no RT group and 96.9% (95% CI, 94.3%99.4%) in the RT group [HR = 1.59 (0.653.89)] (Figure 1); it is important to note that, among the 324 patients in both groups with primary carcinoma less than 1 cm in diameter, only one developed overt axillary metastases (0.3%).
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Discussion |
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It is for these reasons that we considered it important to evaluate, in a prospective study, the outcome of patients with early breast cancer and no palpable axillary nodes treated without axillary dissection. As we expected that a considerable number of patients would develop overt axillary metastases during follow-up, we decided to treat half of them with axillary RT to evaluate the ability of this treatment to reduce the rate of overt axillary metastases [20]. The largest experience in axillary RT dates back to the 1950s when simple mastectomy and radiotherapy to axillary nodes was routine treatment in many Scottish centers, following the McWhirter studies [21
]. In a randomized trial, Johansen et al. [22
] showed that irradiation of the axilla may be an acceptable substitute for axillary dissection. In Manchester between 1970 and 1975, 714 stage I patients were randomized to receive either simple mastectomy (n=359) or simple mastectomy followed by axillary RT (n=355). The 5 and 10 year results showed no difference in overall survival, although local-regional recurrences were higher in the no-RT groups [23
]. More recently, primary RT as an alternative to axillary dissection was re-evaluated in a Dutch study [12
] on postmenopausal women with clinically lymph node negative, early stage breast carcinoma all receiving tamoxifen. A low axillary lymph node recurrence rate with only limited late complications was found, suggesting axillary RT was a valid alternative to axillary dissection in selected patients.
The most important finding of this study is the very low rate of overt axillary metastases appearing in patients of both groups during a median of 63 months of follow-up. Only four of the 435 patients of the entire series developed clinically overt axillary metastases (0.7%) (95% CI, 0.1%2.0%). In a series of 458 consecutive patients from the European Institute of Oncology of the same average age and tumor size as the present series [24], axillary involvement was present at histological examination in 112 (24.5%) (95% CI, 20.6%28.7%). Similar rates were found in a more recent study by Viale et al. [25
] giving a realistic rate of 20% of occult axillary metastases in our series. Applying this rate, 43 of the 214 patients assigned to the no RT group should have microscopic axillary node involvement and would therefore be expected to develop axillary metastases during follow-up; and assuming that axillary RT would sterilize 80% occult nodal metastases, we expected about 10 recurrences in axillary RT group. The rate of axillary metastases in the axillary RT group (1/221) is lower than expected, but may be reasonably attributed to the good sterilizing effect of radiotherapy; however, the low rate (3/214) in patients not receiving axillary treatment may require a different explanation. Although additional cases of axillary involvement may still appear in the future, at present, the number of axillary metastases in the no axillary RT arm appears lower than expected. Most of these patients received long-term tamoxifen, consonant with the high proportion (80.8%) positive for estrogen receptors, and certainly this treatment is partially responsible for the low rate of overt axillary diseases. Moreover, the RT field to the breast might have encompassed the lowest portion of the axilla with minimal irradiation of first level axillary nodes, with a possible limited reduction of the risk of overt axillary metastases. Finally, we have to consider that more than half of the patients had non-palpable carcinomas, so that the series considered here is represented by a subgroup of patients with good prognosis.
However, a reasonable hypothesis may be that, in a certain percentage of cases, occult cancer cells in the lymph nodes may not progress to overt axillary metastases. This behavior seems common in very small carcinomas: in the study by Greco et al. [11] on breast carcinomas less than 1 cm with the axilla left intact, the rate of overt axillary metastases after 5 years was only 1.8%much lower than expected. The explanation for this behavior may be that axillary involvement in very small breast cancer is mainly micrometastatic in type and micrometastases can remain silent for very long periods; we hypothesize that in many cases they might never develop into clinically overt metastases.
When designing this study, we were aware that avoiding axillary dissection would miss information on the possible involvement of axillary nodes, which is an important prognostic factor influencing decisions as to the type and timing of adjuvant systemic treatment. However, in view of the small size of the carcinoma and the menopausal age of most patients, we considered that information from the biological parameters of the primary carcinoma would be adequate. We thus decided to administer tamoxifen to all women with positive estrogen receptors, and chemotherapy to patients with estrogen negative, grade 3, high proliferation rate tumors. With this indication, we administered adjuvant systemic treatments (mainly tamoxifen) to 364 (84%) of our patients and only 66 women (15%) did not receive any post-operative treatment. This policy is in line with that proposed in the S. Gallen Consensus document [8].
Distant metastases were rare in the present series, with breast cancer mortality at 2.5% (95% CI, 1.3%4.5%) no doubt attributable to the small size of cancers included in this study, and also in line with the observation that a high proportion of patients had favorable prognostic markers as determined on the primary carcinoma (Table 1).
The very low incidence of axillary metastases in our series makes any statistical evaluation of the role of axillary radiotherapy in an untouched axilla impossible. However, the fact that in the axillary RT group only one patient developed overt axillary metastases seems to show the efficacy of RT as a protective factor.
If our results are confirmed by longer follow-up, the implications are that axillary dissection might be avoided in patients with very small cancers without palpable nodes. However, data rapidly accumulating in the literature indicate that the method of sentinel node biopsy will be the approach of choice in patients with early breast cancer and a clinically negative axilla [2628
]. The data from this study suggest that the indication for sentinel node biopsy in postmenopausal women with very small breast cancers might be revised.
To conclude, the findings of this randomized trial show: first that the rate of axillary metastases appearing in women treated by breast conservation without any axillary treatment is much lower than expected, leading to the hypothesis that occult axillary metastases might not progress to overt clinical metastases, and secondly, that occult metastases can be kept under control by axillary RT.
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Acknowledgements |
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The following collaborators of the Italian Oncological Senology Group (Griso) actively contributed to the study: F. Nolè, M. Aapro, Istituto Europeo di Oncologia, Milan; M. Rinaldo, P. Frezza, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale, Naples; L. Orzalesi, R. Simoncini, Università degli Studi, Florence; M. P. Mano, R. Bordon, C. Cosuccia, M. Sacco, M. Donadio, Ospedale S. Anna e le Molinette, Turin; A. R. Vento, P. Latini, Azienda Ospedaliera, Perugia; M. Fumagalli, G. Finzi, Città di Parma; C. Lo Castro, L. Tardone, G. Ausili, Università Sacro Cuore, Rome; M. Limonta, M. Colombo, Ospedale di Lecco; P. Lotta, B. Agostara, Ospedale Oncologico Maurizio Ascoli, Palermo; S. Modena, B. Carrara, M. Romano, Policlinico GB Rossi, Verona.
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Notes |
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Received for publication August 2, 2004. Revision received October 25, 2004. Accepted for publication October 26, 2004.
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