Alberto Luini

Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes

BACKGROUND Axillary lymph-node dissection is an important staging procedure in the surgical treatment of breast cancer. However, early diagnosis has led to increasing numbers of dissections in which axillary nodes are free of disease. This raises questions about the need for the procedure. We carried out a study to assess, first, whether a single axillary lymph node (sentinel node) initially receives malignant cells from a breast carcinoma and, second, whether a clear sentinel node reliably forecasts a disease-free axilla. METHODS In a consecutive series of 163 women with operable breast carcinoma, we injected microcolloidal particles of human serum albumin labelled with technetium-99m. This tracer was injected subdermally, close to the tumour site, on the day before surgery, and scintigraphic images of the axilla and breast were taken 10 min, 30 min, and 3 h later. A mark was placed on the skin over the site of the radioactive node (sentinel node). During breast surgery, a hand-held gamma-ray detector probe was used to locate the sentinel node, and make possible its separate removal via a small axillary incision. Complete axillary lymphadenectomy was then done. The sentinel node was tagged separately from other nodes. Permanent sections of all removed nodes were prepared for pathological examination. FINDINGS From the sentinel node, we could accurately predict axillary lymph-node status in 156 (97.5%) of the 160 patients in whom a sentinel node was identified, and in all cases (45 patients) with tumours less than 1.5 cm in diameter. In 32 (38%) of the 85 cases with metastatic axillary nodes, the only positive node was the sentinel node. INTERPRETATION In the large majority of patients with breast cancer, lymphoscintigraphy and gamma-probe-guided surgery can be used to locate the sentinel node in the axilla, and thereby provide important information about the status of axillary nodes. Patients without clinical involvement of the axilla should undergo sentinel-node biopsy routinely, and may be spared complete axillary dissection when the sentinel node is disease-free.

Radiotherapy after Breast-Preserving Surgery in Women with Localized Cancer of the Breast

BACKGROUND AND METHODS Conservative surgery and radiotherapy have become well-established treatments for breast cancer, and many trials in progress are attempting to define the most acceptable type of procedure. Between 1987 and 1989 we randomly assigned 567 women with small breast cancers (< 2.5 cm in diameter) to quadrantectomy followed by radiotherapy or to quadrantectomy without radiotherapy. All patients underwent total axillary dissection. The median follow-up period was 39 months (range, 28 to 54). RESULTS The incidence of local recurrence was 8.8 percent among the patients treated with quadrantectomy without radiotherapy, as compared with 0.3 percent among those treated with postsurgical radiotherapy (P = 0.001). However, there was a substantial effect of age: patients more than 55 years old who did not receive radiotherapy had a low rate of local recurrence (3.8 percent). The four-year overall survival was similar in the two treatment groups. CONCLUSIONS Administering radiotherapy after quadrantectomy reduces the risk of local recurrence in women with small cancers of the breast, but radiotherapy may not be necessary in elderly women.

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised controlled trial

BACKGROUND For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm. METHODS In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293. FINDINGS Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection. INTERPRETATION Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. FUNDING None.

Breast conservation is the treatment of choice in small breast cancer: Long-term results of a randomized trial

From 1973 to 1980, 701 women with small breast cancer (less than 2 cm in diameter) were randomized into two different treatments. 349 patients received classic Halsted mastectomy and 352 patients received quadrantectomy, axillary dissection and radiotherapy on the ipsilateral breast. 24.6% of the patients in the mastectomy group and 27.0% of the patients in the conservation group had axillary metastases. Overall 10 year survival was 76% in the Halsted patients and 79% in the quadrantectomy patients; 13 year survival was 69% and 71%, respectively. No differences were observed after analysis by site and size of the primary tumour and age of the patients. Patients with positive axillary nodes had consistently better survival curves in the quadrantectomy group compared with the Halsted group (not significant). Among the quadrantectomy patients there were 11 local recurrences (with 4 deaths) while among the Halsted patients, 7 had local recurrences (5 deaths). There were 19 cases of contralateral breast carcinomas in the quadrantectomy group and 20 in the Halsted group. At 16 years from the beginning of the trial no evidence of oncogenic radiation risk was observed. In patients with small size carcinomas total mastectomy should have no role.

Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients

Breast conservation has become well-established in the treatment of early mammary carcinoma. However, a standardised treatment modality has not emerged. We have analysed the data from 1,973 patients treated in three consecutive randomised trials by four different radiosurgical procedures: Halsted mastectomy, quadrantectomy plus radiotherapy, lumpectomy plus radiotherapy, and quadrantectomy without radiotherapy, to compare the outcomes of these procedures in terms of local recurrence rate and overall survival. Eligibility criteria were similar in the three trials, and comparability between the four subgroups was excellent. Median follow-up for all patients was 82 months. The annual rates of local recurrence varied markedly according to the treatment. Patients treated with Halsted mastectomy and quadrantectomy plus radiotherapy had low annual rates of local recurrence (0.20 and 0.46, respectively) while both lumpectomy plus radiotherapy and quadrantectomy without radiotherapy had significantly higher rates (2.45 and 3.28, respectively). Patients under 45 years of age had a much higher incidence of local recurrences, while in women over 55 years local recurrences were much less frequent. Overall survival curves were identical in the four groups of patients, so that the three breast conserving radiosurgical procedures had the same survival rates as Halsted mastectomy. However, local recurrence rates were markedly influenced by the treatment method, patient age and specific histological features.

Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study.

Objective:Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. Methods:From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). Results:The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3–15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). Conclusions:Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node.

Quadrantectomy versus lumpectomy for small size breast cancer

Between 1985 and 1987 quadrantectomy plus external radiotherapy and lumpectomy plus external and interstitial radiotherapy were compared in a randomized trial of patients with small carcinomas of the breast. Quadrantectomy involves excision of 2-3 cm of normal tissue around the tumour plus the removal of a sufficiently large portion of overlying skin and underlying fascia whilst lumpectomy removes only the tumour mass with a narrow margin of normal tissue. Patients in both groups also received total axillary dissection. 705 cases were evaluable, 360 quadrantectomies and 345 lumpectomies. No differences in distant metastases and survival were observed in the two groups. However, lumpectomy patients had a much higher frequency of local recurrences (7.0 vs. 2.2%). Since a local recurrence needs a second operation and creates severe psychological distress to the patient, conservative surgical procedures should include generous excision of normal tissue around the primary carcinoma plus intensive postoperative radiotherapy.

Chemotherapy Is More Effective in Patients with Breast Cancer Not Expressing Steroid Hormone Receptors A Study of Preoperative Treatment

Purpose: The purpose of this research was to identify factors predicting response to preoperative chemotherapy. Experimental Design: In a large volume laboratory using standard immunohistochemical methods, we reviewed the pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0–2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status [absent (0% of the cells positive) versus expressed], clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered. Results: High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P < 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P < 0.0001), clinical tumor size <5 cm (P < 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20–8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09–5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28–4.54; P < 0.0001). Conclusions: Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.

Comparative Study of Surgical Margins in Oncoplastic Surgery and Quadrantectomy in Breast Cancer

BackgroundOncoplastic surgery for breast cancer is a novel concept that combines a plastic surgical procedure with breast-conserving treatment to improve the final cosmetic results. The aim of this study was to evaluate the oncological safety of oncoplastic procedures by studying the status of the surgical margins of the excised tumor specimen in comparison with standard quadrantectomies.MethodsThirty consecutive breast cancer patients undergoing oncoplastic surgery (group 1) and 30 patients undergoing standard quadrantectomy (group 2) were prospectively studied with regard to the stage of breast cancer, the surgical procedures performed, the volume of breast tissue excised, and the histopathology of the tumor specimen, with specific details on surgical margins.ResultsPatients who underwent oncoplastic surgery (group 1) were younger (mean age, 48.73 years) than patients who had a classic quadrantectomy (group 2; mean age, 55.76 years; P = .022). The mean volume of the excised specimen in group 1 was 200.18 cm3, compared with 117.55 cm3 in group 2 (P = .016). Surgical margins were negative in 25 cases out of 30 in group 1 and 17 out of 30 in group 2 (P = .05). The average length of the surgical margin was 8.5 mm in group 1 and 6.5 mm in group 2, but the difference was not statistically significant (P = .074).ConclusionsOncoplastic surgery adds to the oncological safety of breast-conserving treatment because a larger volume of breast tissue can be excised and a wider negative margin can be obtained. It is especially indicated for large tumors, for which standard breast-conserving treatment has a high probability of leaving positive margins.

Distribution of axillary node metastases by level of invasion. An analysis of 539 cases

Five hundred and thirty‐nine patients with carcinoma of the breast treated with total axillary dissection and with positive axillary nodes were evaluated. The total number of lymph nodes removed was 11,082, with an average of 20.5 nodes per patient. The average number of lymph nodes at the first level was 13.8, at the second level 4.5, at the third level 2.2. The average number of nodes was 20.7 in cases treated with Halsted mastectomy, 20.9 with total mastectomy and axillary dissection, 20.3 with quadrantectomy and axillary dissection. Of 3259 metastatic nodes, 64 were site of micrometastases; 797 were partially involved, 441 were totally involved and 1957 were site of metastases with extracapsular invasion. In 314 (58.2%) the first level only was involved, in 117 cases (21.7%) metastases were present at the first and second level, whereas in 88 cases (16.3%) all the three levels were sites of metastases. Only 20 cases showed skipping distribution. In 1.5% of the cases the first level was skipped by metastases, in 0.4% the first and second levels were both skipped. The predicting value of the first level is considerable: when the nodes of the first level are clear the chances that metastatic nodes are present at the second and third levels are negligible. When the nodes at the first level are positive, the chances that metastases are also present at the higher levels are of the order of 40.0%. Cancer 59:682‐687, 1987.