Sentinel node biopsy compared with complete axillary dissection for staging early breast cancer with clinically negative lymph nodes: results of randomized trial.

BACKGROUND: Sentinel lymph node (SLN) staging is currently used to avoid complete axillary dissection in breast cancer patients with negative SLNs. Evidence of a similar efficacy, in terms of survival and regional control, of this strategy as compared with axillary resection is based on few clinical trials. In 1998, we started a randomized study comparing the two strategies, and we present here its results. MATERIALS AND METHODS: Patients were randomly assigned to sentinel lymph node biopsy (SLNB) and axillary dissection [axillary lymph node dissection (ALND arm)] or to SLNB plus axillary resection if SLNs contained metastases (SLNB arm). Main end points were overall survival (OS) and axillary recurrence. RESULTS: One hundred and fifteen patients were assigned to the ALND arm and 110 to the SLNB arm. A positive SLN was found in 27 patients in the ALND arm and in 31 in the SLNB arm. Overall accuracy of SLNB was 93.0%. Sensitivity and negative predictive values were 77.1% and 91.1%, respectively. At a median follow-up of 5.5 years, no axillary recurrence was observed in the SLNB arm. OS and event-free survival were not statistically different between the two arms. CONCLUSIONS: The SLNB procedure does not appear inferior to conventional ALND for the subset of patients here considered.

The role of axillary lymph node dissection in breast cancer patients with sentinel lymph node micrometastases.

AIM: To identify by means of clinical and histopathological features a subset of breast cancer patients with sentinel lymph-node (sN) micrometastases and metastatic disease confined only to the sN in order to spare them an unnecessary axillary lymph node dissection (ALND). MATERIALS AND METHODS: From January 1998 to December 2004, 116 patients with sN micrometastases underwent standard ALND for early-stage (T1-2 N0 M0) invasive breast cancer; clinical and histopathologic parameters were prospectively collected and evaluated by means of univariate and logistic regression analysis in order to identify which patients with sN micrometastases were free of metastasis in axillary non-sN. RESULTS: Sixteen of 116 patients with sN micrometastases had tumour involvement of non-sN, with six and 10 patients having non-sN micrometastases and macrometastases, respectively. None of 19 patients with primary tumour measuring

A pilot study of accelerated cyclophosphamide, epirubicin and 5-fluorouracil plus granulocyte colony stimulating factor as adjuvant therapy in early breast cancer.

32 consecutive early breast cancer patients were treated to evaluate the feasibility of an accelerated CEF regimen (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and 5-fluorouracil 600 mg/m2) given intravenously every 2 weeks for six cycles together with granulocyte colony stimulating factor, 5 micrograms/kg/day subcutaneously from day 4 to day 11. One hundred and eighty two out of 192 planned cycles (95%) were administered. Toxicity was mild: no cases of grade IV non-haematological toxicity and only one episode of grade IV granulocytopenia were observed. Delays or dose reductions of anti-neoplastic drugs occurred in 14 cycles (7.7%). The mean duration of six cycles of treatment was 71 days (planned 70) and 93% of average planned dose intensity was actually administered. The short course CEF therapy is a feasible, well tolerated outpatient chemotherapy regimen, allowing a 46% increase in dose intensity compared with a standard CEF regimen given every 3 weeks. A randomised study comparing this regimen to a standard CEF regimen is now in progress in early breast cancer patients.

Locally advanced non-metastatic breast cancer: analysis of prognostic factors in 125 patients homogeneously treated with a combined modality approach.

125 stage III breast cancer patients, including 51 cases of inflammatory carcinoma, were treated with the following combined modality approach: three courses of primary 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) chemotherapy followed by locoregional treatment and subsequent adjuvant chemotherapy consisting of three courses of FAC alternating with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Clinical response to primary FAC was 65% (complete 10%). Residual tumour mass in the mastectomy specimen was > 1 and < or = 1 cm in 82 and 18% of cases, respectively. Complete pathological response following primary chemotherapy was achieved in only 3.5% of cases. After primary FAC and local treatment, 97% of patients were disease-free. Overall survival (S) and progression-free survival (PFS) at 5 years were 56 and 34%, respectively. Univariate analysis showed that age, receptor status and clinical and pathological response to primary chemotherapy did not appear to influence treatment outcome significantly, whereas stage, presence of inflammatory disease and number of involved nodes had a significant impact on both S and PFS.

Prognostic role of lymph-node level involvement in patients undergoing axillary dissection for breast cancer.

AIMS: Clinical records of patients undergoing surgery for breast cancer were reviewed in order to evaluate the prognostic role of lymph-node level involvement. METHODS: From 1982 to 1991, 1143 patients had radical mastectomy or conservative surgery with total axillary dissection: 461 patients of mean age 57.1 years (range: 25-89 years) were lymph-node positive (pN1); 369 patients (80%) had radical mastectomy; and 92 patients (20%) had conservative treatment plus post-operative radiotherapy, with the same mean number (n = 16) of lymph nodes collected in the surgical specimen. Data were analysed for the number of positive lymph nodes and level of involvement. RESULTS: Level I, Levels I + II and Levels I + II + III were involved in 44.9, 18 and 21.4% of patients, respectively; 'skip metastases' occurred in 72 of 461 pN1 patients (15.5%). A univariate analysis showed that prognosis was directly related to the number of levels involved (P < 0.001), and skip metastases had the same prognostic role as Level I involvement. The numbers of involved lymph-node levels and metastatic lymph nodes were well correlated; multivariate analysis showed that involvement of Levels I and III was independently correlated with prognosis. After adjustment for age and number of positive lymph nodes, the number of involved lymph-node levels was an independent prognostic factor, with highest predictability when all three lymph-node levels were positive (P = 0.009). CONCLUSIONS: The prognostic value of lymph-node status should be defined not only by the number of metastatic lymph nodes, but also by the number of levels of involvement.

Surgical complications related to peri-operative adjuvant chemotherapy in breast cancer. Results of a prospective, controlled, randomized clinical trial.

From May 1985 to June 1992, 375 patients were enrolled in a prospective controlled randomized clinical trial of peri-operative adjuvant chemotherapy (PAC) associated with long-term adjuvant chemo-endocrinotherapy in order to test the effectiveness of reducing the time interval between surgery and chemotherapy. The short-term surgical complications related to PAC are reported in order to verify whether such treatment might negatively affect the results of breast cancer surgery. One hundred and eighty-nine patients were randomly assigned to the peri-operative treatment, and 186 to the control group. Patients undergoing PAC received one course of cyclophosphamide (600 mg/sqm), epidoxorubicin (60 mg/ sqm), and 5-fluorouracil (600 mg/sqm) (CEF) within 48-72 h following surgery. Pathologically node-positive (N+) patients, who were given peri-operative CEF, had five further cycles of CEF alternated with six cycles of CMF (cyclophosphamide 600 mg/sqm, methotrexate 40 mg/sqm, and 5-fluorouracil 600 mg/sqm). All the other N+ patients received six cycles of CEF alternated with six cycles of CMF, starting within 30 days of surgery. No significant difference in post-operative morbidity was observed as regards median hospital stay (8 days), number of outpatient dressings (3.5 vs 3), seroma (51 (26.9%) vs 45 (24.2%)), lymphatic drainage (400 ml vs 409 ml), and post-operative infections, both local (10 vs 9) and in extraoperative foci (6 vs 7), in the study and control group, respectively. The toxicity of the peri-operative CEF was mainly gastrointestinal (nausea and vomiting, 55%; stomatitis, 3%), with only a small percentage (9%) reaching grades III-IV. Hair loss was the other main side effect (55%) with baldness in only 3%. Post-operative complications following radical breast cancer surgery seem to be primarily related to operative details (type of incision, accurate nerve-sparing technique, bleeding control, closure of subcutaneous and skin, drainage, aseptic technique) rather than to the one course of PAC.

Pre-operative localization of non-palpable lesions in breast cancer by charcoal suspension.

The use of preoperative localization procedures for non-palpable breast lesions (NPBL) is becoming more and more widespread, increasing the detection of early breast cancers. From October 1987 to July 1992, at our Institution, 253 patients (pts) with clinically non-palpable lesions underwent surgical treatment. Of the 253 pts, the lesions have been localized in 95 cases by a needle system, and in the other 158 cases by a dye injection of a 3% sterile charcoal suspension using stereotactic method (118 cases) or sonography (40 cases). The patients' mean age was 53 years (range 30-75). Mammography revealed regular opacities in 133 cases, clustered microcalcification in 75, diffuse microcalcification in 24, opacities with irregular borders in nine and opacities with internal microcalcifications in 12. The histological findings showed benign breast disease in 175 cases (69.2%), borderline breast disease in 23 (9.1%) and malignancy in 55 (21.7%). The benign/malignant/borderline lesions ratio was 3.2:1. The majority (70%) of these malignant lesions were small cancers (less than 1 cm in diameter) and without lymph-node involvement. The biopsy cost (benign/malignant/borderline ratio, patients discomfort and cosmetic result) has been acceptable.

A phase I study of recombinant interleukin-2 intraperitoneal infusion in patients with neoplastic ascites: toxic effects and immunologic results.

A phase I study to evaluate the use of i.p. infusion of recombinant interleukin-2 (rIL-2) was planned. The following dose levels were calculated: 0.1, 0.3, 1.0, 3.0 and 10 mg/m2/day for 14 days, but only the second levels were reached. In this trial the acute toxic effects at this dosage included cardiac ischemia, transient liver impairment and septic peritonitis. The maximum tolerated dose (MTD) was 0.3 mg/m2/day for 14 days. In addition, two patients developed peritoneal fibrosis. No objective responses were observed. Therefore, in order to explore the biological activity of low (nontoxic) doses, three patients (one untreated and two previously treated with rIL-2) were infused with 0.01 and 0.03 mg/m2/day for 7 days. Potentiation of cytolytic activities in peritoneal lymphocytes and activation of a lymphokine cascade in the ascitic fluid were observed at doses ranging from 0.03 mg/m2/day to 0.3 mg/m2/day. These findings in association with the toxic effects observed at the MTD suggest the use of the minimum effective dose for future locoregional immunotherapeutic protocols.

Localization of the sentinel lymph node in breast cancer by combined lymphoscintigraphy, blue dye and intraoperative gamma probe.

Axillary lymph node status represents the most important prognostic factor in patients with operable breast cancer. A severe limitation of this technique is the relatively high rate of false negative sentinel lymph nodes (>5%). We studied 284 patients suffering from breast cancer; 264 had T1 tumors (16 T1a, 37 T1b and 211 T1c), while 20 had T2 tumors. All patients underwent lymphoscintigraphy 18-h before surgery. At surgery, 0.5 mL of patent blue violet was injected subdermally, and the sentinel lymph node (SN) was searched by gamma probe and by the dye method. The surgically isolated SN was processed for intraoperative and delayed examinations. The SN was successfully identified by the combined radioisotopic procedure and patent blue dye technique in 278/284 cases (97.9%). Analysis of the predictive value of the SN in relation to the status of the axillary lymph nodes was limited to 191 patients undergoing standard axillary dissection irrespective of the SN status. Overall, 63/191 (33%) identified SNs were metastatic, the SN alone being involved in 37/63 (58.7%) patients; a positive axillary status with negative SN was found in 10/73 (13.7%) patients with metastatic involvement. In T1a-T1b patients the SN turned out to be metastatic in 9/53 patients (17.0%). In 7/9 patients the SN was the only site of metastasis, while in 2/9 patients other axillary lymph nodes were found to be metastatic in addition to the SN. None of the 44 patients in whom the SN proved to be non-metastatic showed any metastatic involvement of other axillary lymph nodes. Our results demonstrate a good predictive value of SN biopsy in patients with breast cancer; the predictive value was excellent in those subjects with nodules smaller than 1 cm.

[A controlled-case study on risk factors in tumors of the oral cavity. Perspectives and indications for early diagnosis]. / Uno studio caso-controllo su fattori di rischio dei tumori del cavo orale. Prospettive ed indicazioni per la diagnostica precoce.

The literature on carcinomas of the oral cavity shows general agreement that alcohol and smoking are risk factors. Only a few authors blame poor hygiene. The retrospective survey conducted in Genoa aimed to evaluate the relative importance of these risk factors, by means of a case-controlled study linking a specific risk factor to a specific condition. 98 histologically confirmed cases were hospitalised in 1979-80. A similar survey was conducted on a control group. Smoking and alcohol, often both together, were found to be the most significant aetiopathogenetic risk factors in the oncological pathology of the oral cavity.

Surgical treatment of thyroid cancer.

Surgery is the treatment of choice for thyroid cancer, often followed by I131 and thyroid hormone to control the local residual tumor and distant metastasis. Hundred and sixty-two patients with thyroid disease underwent surgery at the Division of Surgical Oncology of the Cancer Institute in Genoa. Thirty cases presented no malignant hot thyroid nodules, 37 of the other 132 cases were cancers (28%). In 23 cases (62%), the pathological diagnosis was papillary carcinoma, in ten cases (27%) follicular carcinoma, in four (11%) medullary carcinoma. In 13 cases (35%) (ten papillary carcinoma, two follicular carcinoma, one medullary carcinoma) the lesion was multicentric. Our data suggest that total thyroidectomy, performed in two steps, in most cases does not carry important post-operative morbidity but offers the greatest potential for cure. In our cases only one patient died (of the cancer). After radical surgery it is possible to detect and treat metastases by I131.

Retroperitoneal infectious myositis.

A case of retroperitoneal infectious myositis is described. The symptoms of infectious myositis may be confused with those of other more frequent soft tissue pathologies (haematoma and sarcomata). This infection is more frequent in countries with a tropical climate. The most frequent aetiological agent is Staphylococcus aureus. This paper reports on the diagnostic and therapeutic problems of this disease as recently observed at the Division of Surgical Oncology of the National Cancer Institute in Genoa.

Non palpable breast lesions: preoperative sonographic localization.

From 1987 to 1992 at our Institute, 253 patients with non palpable breast lesions (NBPL) underwent a surgical excision. Fifty-one lesions (19.7%) were localized by an injection of a sterile 3% charcoal suspension under sonographic guide. The sonographic features of NBPL were classified as follows: positive in one case (2%), doubtful in 31 cases (60%) and negative in 19 cases (38%). According to our data the preoperative sonographic localization is a useful alternative procedure to stereotactis mammography in case of breast masses and/or areas of increased tissue density or distorted breast architecture.

[The surgery of breast carcinoma. 10 years of activity]. / La chirurgia del carcinoma mammario. Dieci anni di attività.

From 1981 to 1990, 1003 stage I-II breast cancers underwent surgery at the Division of Surgical Oncology of National Institute for Cancer Research of Genoa. This study described the clinical and pathologic features of these breast cancers. Radical mastectomy was performed in 73.8% of cases and conservative surgery in 26.2% of cases. In the last years the number of conservative treatment has increased. Related to size of tumour, in 1991 80.4% of pT1 performed a conservative surgery. The choice of type of surgery for pT2 tumours depended on the choice of patient and the ratio breast size and tumour size. The five-year overall survival was 85.8% in the group of conservative surgery and 65.3% in the group of radical surgery. The overall survival and relapse free survival have been calculated by Kaplan-Meyer method. Actuarial survival curves were computed according to type of surgery, tumor size, nodal status, hormonal receptors. In our experience the size of tumour was an important prognostic factor. The five years, overall survival was 80.7% in pT1 tumours and 67% in pT2-pT3 tumours (p = 10(-6)). The five-year overall survival in negative nodes patients was 80.5%. Conversely in patients with more than ten nodal metastases was 29.5%. The data reported in the present study were no different as in previous studies.

A risk score model predictive of the presence of additional disease in the axilla in early-breast cancer patients with one or two metastatic sentinel lymph nodes.

BACKGROUND: Axillary lymph node dissection (ALND) in early-breast cancer patients with positive sentinel node (SLN+) may not always be necessary. AIMS: To predict the finding of ≥1 metastatic axillary node in addition to SLN+(s); to discriminate between patients who would or not benefit from ALND. METHODS: Records of 397 consecutive patients with 1-2 SLN+s receiving ALND were reviewed. Clinico-pathological features were used in univariate and multivariate analyses to develop a logistic regression model predictive of the risk of ≥1 additional axillary node involved. The discrimination power of the model was quantified by the area under the receiver operating characteristic curve (AUC) and validated using an independent set of 83 patients. RESULTS: In univariate analyses, the risk of ≥1 additional node involved was correlated with tumor size, grade, HER-2 and Ki-67 over-expression, number of SLN+s. All factors, but Ki-67, retained in multivariate regressions were used to generate a predictive model with good discriminating power on both the training and the validation sets (AUC 0.73 and 0.75, respectively). Three patient groups were defined based on their risk to present additional axillary burden. CONCLUSIONS: The model identifies SLN+-patients at low risk (≤15%) who could reasonably be spared ALND and those at high risk (>75%) who should receive ALND. For patients at intermediate risk, ALND appropriateness could be individually evaluated based on other clinico-pathological parameters.

Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes.

BACKGROUND: Feasibility and accuracy of sentinel node biopsy (SLNB) after the delivery of neo-adjuvant chemotherapy (NAC) is controversial. We here report our experience in NAC-treated patients with locally advanced breast cancer and clinically positive axillary nodes, and compare it with the results from our previous randomized trial assessing SLNB in early-stage breast cancer patients. PATIENTS AND METHODS: Sixty-four consecutive patients with large infiltrating tumor and clinically positive axillary nodes received NAC and subsequent lymphatic mapping, SLNB and complete axillary lymph node dissection (ALND). The status of the sentinel lymph node (SLN) was compared to that of the axilla. RESULTS: At least one SLN was identified in 60 of the 64 patients (93.8%). Among those 60 patients, 37 (61.7%) had one or more positive SLN(s) and 23 (38.3%) did not. Two of the patients with negative SLN(s) presented metastases in other non-sentinel nodes. SLNB thus had a false-negative rate, a negative predictive value and an overall accuracy of 5.1%, 91.3% and 96.7%, respectively. All these values were similar to those we reported for SLNB in the settings of early-stage breast cancer. CONCLUSION: SLNB after NAC is safe and feasible in patients with locally advanced breast cancer and clinically positive nodes, and accurately predicts the status of the axilla.

Intra-operative evaluation of the sentinel lymph node for T1-N0 breast-cancer patients: always or never? A risk/benefit and cost/benefit analysis.

AIM: To investigate whether omitting intra-operative staging of the sentinel lymph node (SLN) in T1-N0 breast-cancer patients is feasible and convenient because it could allow a more efficient management of human and logistic resources without leading to an unacceptable increase in the rate of delayed axillary lymph node dissection (ALND). METHODS: According to the experimental procedure, T1a-T1b-patients were to not receive any intra-operative SLN evaluation on frozen sections (FS). In all T1c-patients, the SLN was macroscopically examined; if the node appeared clearly free of disease, no further intra-operative assessment was performed; if the node was clearly metastatic or presented a dubious aspect, the pathologist proceeded with analysis on FS. T2-patients, enrolled in the study as reference group, were treated according to the institutional standard procedure; they all received SLN staging on FS. RESULTS: The study included 395 T1-N0-patients. Among the 118 T1a-T1b-patients whose SLN was not analyzed at surgery, 12 (10.2%) were recalled for ALND. In the group of 258 T1c-patients, 112 received SLN analysis on FS and 146 did not. An SLN falsely negative either at macroscopic or FS examination was found in 33 (12.8%) cases. Overall, the rate of recall for ALND was 11.6% as compared to 8.4% in T2-patients. Using the experimental protocol, the institution reached a 9.6% cost saving, as compared to the standard procedure. CONCLUSIONS: Omission of SLN intra-operative staging in T1-N0-patients is rather safe. It provides the institution with both management and economical advantages.