Tailoring the optimal duration of the extended adjuvant endocrine therapy in patients with early-stage breast cancer. A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Controversy exists regarding the optimal duration of the extended adjuvant endocrine treatment (ET) in patients with early-stage breast-cancer (eBC). We performed a systematic review and trial-level meta-analysis of all randomized clinical trials (RCTs) comparing a "limited-extended" adjuvant ET (defined as more than 5 but less than 7.5 years of treatment overall) versus a "full-extended" adjuvant ET (defined as more than 7.5 years of treatment overall) in eBC. METHODS: To be eligible, RCTs had to i) compare a "limited-extended" adjuvant ET versus a "full-extended" adjuvant ET in patients with eBC; and ii) report disease-free survival (DFS) hazard ratio (HR) according to the disease nodal-status [i.e., nodal-negative (N-ve) versus nodal-positive (N + ve)]. The primary endpoint was to assess the difference in efficacy of full-versus limited-extended ET, measured in terms of the difference in DFS log-HR, according to the disease nodal-status. Secondary endpoint was the difference in efficacy of full-versus limited-extended ET according to tumor size (i.e., pT1 vs pT2/3/4), histological grade (i.e., G1/G2 vs G3), patients' age (i.e., ≤60 vs > 60 years) and previous type of ET (i.e., aromatase inhibitors vs tamoxifen vs switch strategy). RESULTS: Three phase III RCTs fulfilled the inclusion criteria. A total of 6689 patients were included in the analysis, of which 3506 (53%) had N + ve disease. The full-extended ET provided no DFS-benefit as compared with the limited-extended ET in patients with N-ve disease (pooled DFS-HR = 1.04, 95%CI: 0.89 to 1.22; I2 = 18%). Conversely, in patients with N + ve disease the full-extended ET significantly improved DFS, with a pooled DFS-HR of 0.85 (95%CI: 0.74 to 0.97; I2 = 0%). There was a significant interaction between the disease nodal-status and the efficacy of the full-versus limited-extended ET (p-heterogeneity = 0.048). The full-extended ET provided no significant DFS-benefit as compared with the limited-extended ET in all the other subgroups analyzed. CONCLUSIONS: Patients with eBC and N + ve disease can obtain a significant DFS-benefit from the full-extended as compared with the limited-extended adjuvant ET.

Accelerated partial breast irradiation in early breast cancer: focus on intraoperative treatment with electrons (ELIOT).

Wide tumor resection plus postoperative whole breast irradiation is standard treatment for early breast cancer. Irradiation decreases recurrence rates, but may cause poor cosmesis, breast pain, and cardiac and lung toxicity. Accelerated partial breast irradiation is increasingly used in the hope of increasing convenience, decreasing sequelae and maintaining cure rates. Intraoperative radiotherapy with electrons is an attractive accelerated partial breast irradiation technique because collimator placement is under the direct control of the surgeon who removes the tumor, the skin is spared, shielding protects the chest wall and complete irradiation can be given in a single intraoperative session (avoiding 5-7 weeks of whole breast irradiation). Intraoperative radiotherapy with electrons seems as safe as whole breast irradiation; however, long-term results on local control and survival are not available yet.

The Changing Face of Mastectomy (from Mutilation to Aid to Breast Reconstruction).

Breast cancer is the most common cancer in women. Primary treatment is surgery, with mastectomy as the main treatment for most of the twentieth century. However, over that time, the extent of the procedure varied, and less extensive mastectomies are employed today compared to those used in the past, as excessively mutilating procedures did not improve survival. Today, many women receive breast-conserving surgery, usually with radiotherapy to the residual breast, instead of mastectomy, as it has been shown to be as effective as mastectomy in early disease. The relatively new skin-sparing mastectomy, often with immediate breast reconstruction, improves aesthetic outcomes and is oncologically safe. Nipple-sparing mastectomy is newer and used increasingly, with better acceptance by patients, and again appears to be oncologically safe. Breast reconstruction is an important adjunct to mastectomy, as it has a positive psychological impact on the patient, contributing to improved quality of life.

High-intensity focused ultrasound ablation: effective and safe therapy for solid tumors in difficult locations.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of ultrasound-guided high-intensity focused ultrasound therapeutic ablation of solid tumors in difficult locations. SUBJECTS AND METHODS: A procedure was performed with a focused ultrasound tumor therapeutic system which provides real-time ultrasound guidance. All patients underwent MDCT or MRI, and some patients underwent PET/CT. From November 2007 through April 2009, 31 patients with 38 lesions of the liver and pancreas in difficult locations were treated. Six patients had hepatocellular carcinoma, 13 patients had hepatic metastasis from colorectal cancer, two had hepatic metastases of breast cancer, two had hepatic metastasis of neuroendocrine tumors, one patient had lymph node metastasis of breast cancer at the hepatic hilum, six patients had pancreatic cancer, and one patient had a neuroendocrine tumor. Difficult location was defined as tumor adjacent to a main blood vessel, the heart, the gallbladder and bile ducts, the bowel, or the stomach. RESULTS: The mean diameter of tumors was 2.7 +/- 1.4 cm. PET/CT, MDCT, or both on the day after one session of high-intensity focused ultrasound treatment showed complete response in all six patients with hepatocellular carcinoma, the patient with lymph node metastasis, and 22 of 24 patients with hepatic metastasis. The symptoms of all seven patients with pancreatic caner or neuroendocrine tumors were palliated, and PET/CT or MRI showed complete response of six of seven lesions. Portal vein thrombosis occurred after high-intensity focused ultrasound ablation in one patient with pancreatic cancer. No other side effects were detected in a median follow-up period of 12 months. CONCLUSION: According to our short- and long-term follow-up results, ultrasound-guided high-intensity focused ultrasound ablation can be considered a safe and feasible approach to the management of solid tumors in difficult locations.

Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons.

Intraoperative radiotherapy with electrons (ELIOT) after conservative surgery for breast carcinoma was introduced at the IEO in 1999 as a research programme. The results on 1,822 patients treated from January 2000 to December 2008 are reported. Women with unicentric primary breast carcinoma of less than 2.5 cm in the largest diameter were assessed by imaging. All patients were treated with breast-conserving surgery (quadrantectomy). ELIOT was delivered by two mobile linear accelerators immediately after breast resection with a single dose of 21 Gy. Local side effects of ELIOT were mainly liponecrosis (4.2%) and fibrosis (1.8%). After a mean follow-up of 36.1 months, 42 women (2.3%) developed a local recurrence, 24 (1.3%) a new primary ipsilateral carcinomas and 26 (1.4%) distant metastases as first event. Forty-six women died (2.5%), 28 for breast carcinoma and 18 for other causes. Five- and ten-year survivals were, respectively, 97.4 and 89.7%. ELIOT appears a promising feature in early breast cancer treated with breast conserving surgery, reducing the exposure of normal tissues to radiations and shortening the radiation course from 6 weeks to one single session.

Male breast cancer.

Diagnosis and treatment modalities for female breast cancer have developed spectacularly in recent years. Unfortunately, this is not the case for male breast cancer. Because the disease is so rare, controlled clinical trials have almost never been performed and treatment is based on findings in women or small series of men. Similarly, while breast cancer in women is diagnosed at an increasingly early stage, male breast cancer is usually diagnosed late, when the chances of cure are diminished. This article reviews what is currently known about male breast cancer, with an emphasis on areas where evidence-based data are scarce. While it is possible that some recent developments in female breast cancer treatment could be applicable to men, but the way forward is to increase awareness of the disease, and for treatment centers to pool patients for inclusion in randomized clinical trials.

High intensity focused ultrasound ablation: a new therapeutic option for solid tumors.

Surgery has been the standard of care in selected cases with solid tumors. However, a majority of patients are unable to undergo surgical resection because of the tumor sites, advanced stages, or poor general condition. High intensity focused ultrasound (HIFU) is a novel non-invasive technique that is capable of producing coagulative necrosis at a precise focal point within the body, without harming overlying and adjacent structures even within the path of the beam. Diagnostic ultrasound was the first imaging modality used for guiding HIFU ablation in the 1990 s. Over the last decade, thousands of patients with uterine fibroids, liver cancer, breast cancer, pancreatic cancer, bone tumors, renal cancer have been treated with ultrasound imaging-guided HIFU (USgHIFU) worldwide. This USgHIFU system [Chongqing Haifu (HIFU) Tech Co., Ltd., Chongqing, China] was first equipped in Asia, now in Europe. Several research groups have demonstrated that HIFU is safe and effective in treating human solid tumors. In 2004, the magnetic resonance guided focused ultrasound surgery (MRgFUS) was approved by the United States Food and Drug Administration (FDA) for clinical treatments of uterine fibroids. We conclude that HIFU offers patients another choice when no other treatment available or when patients refused surgical operation. This technique may play a key role in future clinical practice.

Rethinking TNM: a breast cancer classification to guide to treatment and facilitate research.

The TNM(UICC) classification of breast cancer categorizes tumor size, regional lymph node involvement, and distant metastases. Treatment is influenced by these characteristics, but requires knowledge of several other factors. In fact, effective treatment is dependent on disease extent, hormone receptor status, and other biologic characteristics of the cancer. We propose a new classification [tumor node metastasis (TNM)] that not only includes relevant biologic characteristics and can expand to include others as they are validated but also specifies tumor size exactly (T2.3 indicates a cancer of maximum diameter 2.3 cm), provides more information on regional lymph node involvement, and specifies the site(s) of distant metastases. We also propose abolishing the term "carcinoma" for non-invasive neoplastic conditions and the term "infiltrating" for carcinomas. The new classification is sufficiently similar to the TNM(UICC) classification to permit valid comparison of patients classified by both systems, but is more logical, provides information useful for guiding therapy, and is flexible enough to satisfy present and future clinical and research needs.

The sentinel node biopsy under local anesthesia in breast cancer: advantages and problems, how the technique influenced the activity of a breast surgery department; update from the European Institute of Oncology with more than 1000 cases.

Sentinel lymph node biopsy (SLNB) is a staging technique with a significant impact on patients' quality of life: the oncological effectiveness in a large number of patients affected by breast carcinoma has been already demonstrated, and the clinical research is now focusing on new indication for the biopsy and widespread adoption of the technique. At the European Institute of Oncology we are applying SLNB under local anesthesia: our aim is to improve the management of the disease with low costs for the structure and patients, and to improve patients' acceptance of breast cancer treatments. We are now discussing the impact of the SLNB under local anesthesia on the activity of a breast surgery department. We also present an update of our experience.

Nipple-sparing mastectomy for breast cancer and risk reduction: oncologic or technical problem?

BACKGROUND: We evaluated the risks and benefits of nipple-sparing mastectomy in a multiinstitutional experience in the settings of risk-reducing surgery and breast cancer treatment. STUDY DESIGN: We analyzed data on 123 patients who had undergone nipple-sparing mastectomy with breast reconstruction for prophylaxis (n=55), treatment of breast cancer (n=41), or both (n=27) at four large centers. RESULTS: Median patient age was 45 years (range 22 to 70 years). There were 192 procedures (69 bilateral, 54 unilateral). Forty-four patients had invasive cancer; 20 had ductal carcinoma in situ (DCIS); 4 had phyllodes tumor. In all of these patients, the nipple tissue was cancer free on pathologic review. Median followup was 24.6 months (range 2.0 to 570.4 months). Local recurrence developed in two patients: one had DCIS in the upper-outer quadrant, with 71.8 months of followup; the other's cancer was invasive, in the upper-outer quadrant, with 6 months of followup. Distant metastasis developed in a third patient, who died 50 months after the procedure. Breast cancer developed in two patients after prophylactic mastectomy: one in the upper-outer quadrant at 61.8 months; one in the axillary tail at 24.4 months. No patients had recurrences in the nipple-areolar complex. Necrosis of the nipple was reported in 22 of 192 patients (11%) and it was judged minimal (less than one-third total skin of nipple) in 13 of 22 patients (59%). Overall cosmesis was judged by the patient and surgeon as good to excellent in the majority of patients. Level of satisfaction with cosmetic results was similar between prophylactic and treatment patients. CONCLUSIONS: The risk of local relapse was very low in our series of nipple-sparing mastectomies performed for DCIS or invasive cancer. Nipple-sparing mastectomy in the risk-reducing and breast cancer-treatment settings may be feasible in selected patients and should be the subject of additional prospective clinical trials.

The sentinel node biopsy after previous breast surgery: preliminary results on 543 patients treated at the European Institute of Oncology.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an accurate alternative to complete axillary lymph node dissection (ALND) in clinically node-negative breast cancer patients. A previous breast biopsy has been considered a relative contraindication to SLNB. We examined the accuracy of SLNB by following the axillary relapses after the procedure in patients who had undergone a breast biopsy before SLNB. PATIENTS AND METHODS: Up to December 2003, 4351 patients with the diagnosis of invasive breast cancer underwent SLNB at the European Institute of Oncology. Already, 543 of these patients had undergone a breast biopsy; from June 1997 to January 2004, these patients received SLNB by lymphoscintigraphy performed on the biopsy area. We followed these patients with a clinical assessment every 6 months and instrumental examinations every year, particularly focusing on the research of axillary relapse of disease. RESULTS: In 70.4% of cases, the sentinel node was negative, and only three cases underwent further axillary dissection. The sentinel node was identified in 99% of cases and this was the only positive node in 61.5% of cases with positive axillary nodes. The median follow-up was 2 years; 4 nodal recurrences were observed: 3 axillary lymph node relapses and 1 loco-regional. CONCLUSIONS: SLNB accuracy after a previous breast biopsy is comparable with the results obtained in validation studies. SLNB after a previous breast biopsy can be considered a standard procedure. Lymphoscintigraphy identifies the sentinel node in 99% of patients.

Sentinel lymph node metastasis in microinvasive breast cancer.

BACKGROUND: Ductal carcinoma in situ with microinvasion (DCISM) is a separate pathological entity, distinct from pure ductal carcinoma in situ (DCIS). DCISM is a true invasive breast carcinoma with a well-known metastatic potential. Currently, there is controversy regarding the indication for complete axillary dissection (CAD) to stage the axilla in patients with DCISM. The role of CAD is questioned given its morbidity and reported low incidence of axillary involvement. Sentinel lymph node biopsy (SLNB) may obviate the need for CAD in these patients without compromising the staging of the axilla and the important prognostic information. METHODS: From March 1996 to December 2002, 4602 consecutive patients with invasive breast carcinoma underwent SLN biopsy. Of these, 41 patients with DCISM were selected. RESULTS: Metastasis in the SLN were detected in 4 of 41 (9.7%) patients. Two of the 4 patients had only micrometastasis in the SLN. In three patients, the SLN was the only positive node after CAD. CONCLUSIONS: SLN biopsy should be considered as a standard procedure in DCISM patients. SLNB can detect nodal micrometastasis and accurately stage the axilla avoiding the morbidity of a CAD. Complete AD may not be mandatory if only the SLN contains micrometastatic disease. Informed consent is very important in the decision not to undergo CAD.

Biopsia de la cadena mamaria interna: utilidad en la clasificación por estadios / Biopsy of the internal mammary chain: utility in the classification by stages

La positividad de los ganglios de la cadena mamaria interna, se asocia con peor pronóstico. Con la linfocentelleografía, se ha evidenciado que los ganglios de la cadena mamaria interna, reciben la linfa del área donde se encuentra el tumor. Desarrollamos un estudio piloto donde determinamos: factibilidad en realizar la biopsia, presencia de metástasis y el impacto en el cambio de estadio y la terapia. Realizamos la biopsia de los ganglios de la cadena mamaria interna en 137 pacientes. Luego de la resección del tumor, separamos las fibras del músculo pectoral mayor; la parte medial del músculo fue removida para acceder al espacio subcostal. Se liberó el tejido graso de los vasos mamarios y la pleura. El material obtenido fue mandado para examen histológico. Se encontraron ganglios de la cadena mamaria interna en 122 de los 137 pacientes. 110 fueron negativos y 12 fueron metastáticos. En 4 de los 12 casos, los ganglios axilares o el ganglio centinela fueron negativos y en los 8 casos restantes fueron positivos. Cuatro pacientes presentaron ganglios metastáticos en la cadena mamaria interna y ganglio centinela negativo. Los ganglios de la cadena mamaria interna se pueden resecar desde la incisión de la cirugía conservadora. Procedimiento simple y rápido. Los riesgos son insignificantes. En los doce casos con ganglios de la cadena mamaria interna positivos hubo migración de estadio de N0 (4 casos) o N1 (8 casos) a N3 y estos resultados modificaron el tratamiento. Si la biopsia no se hubiera realizado el estadio habría sido menor del real

Stage migration after biopsy of internal mammary chain lymph nodes in breast cancer patients.

BACKGROUND: Involvement of the internal mammary chain lymph nodes (IMNs) is associated with worsened prognosis in breast cancer. Use of lymphoscintigraphy to visualize sentinel nodes reveals that IMNs often receive lymph from the area containing the tumor. METHODS: We biopsied IMNs in 182 patients because there was radiouptake to the IMNs or because the tumor was located in the medial portion of the breast. After tumor removal, pectoralis major fibers were divided to expose intercostal muscle. A portion of intercostal muscle adjacent to the sternum was removed. Lymph nodes and surrounding fatty tissue in the intercostal space were freed, removed, and analyzed histologically. The pleural cavity was breached in four cases (2.2%), with spontaneous resolution. RESULTS: IMNs were found in 160 (88%) of 182 patients; 146 (94.4%) were negative and 14 (8.8%) were positive. The latter received internal mammary chain radiotherapy. The axilla was negative in 4 of 14 cases and positive in 10. CONCLUSIONS: IMNs can be quickly and easily removed via the breast incision with insignificant risk and no increase in postoperative hospitalization. The patients with a positive IMN migrated from N0 (4 cases) or N1 (10 cases) to N3, prompting modification of both local (radiotherapy to internal mammary chain) and systemic treatment; without IMN sampling, they would have been understaged.

Sentinel lymph node biopsy performed with local anesthesia in patients with early-stage breast carcinoma.

HYPOTHESIS: Sentinel lymph node (SN) biopsy performed with local anesthesia has a positive effect on patients' quality of life and on treatment management for early-stage breast carcinoma. This method represents an interesting development in breast-conserving surgery. DESIGN: We performed SN biopsy with local anesthesia in selected patients to test the feasibility of the technique and its impact on our organization and on patients' quality of life. PATIENTS AND METHODS: From September 2000 to December 2001, we studied 115 patients with a palpable breast tumor (maximum diameter, 2.5 cm). The axilla was clinically negative for metastasis in all cases. RESULTS: Forty-eight patients (41.7%) had SNs that were positive for metastasis. In 20 cases (17.4%), the SN was macrometastatic and in 28 cases (24.3%), it was micrometastatic (diameter <2 mm). The SN was negative for metastasis in 66 cases (57.4%). In 1 case, the histologic examination revealed the presence of a non-Hodgkin B-cell lymphoma. The complete axillary dissection performed in the subgroup of patients with macrometastatic SNs showed that in 9 cases (45%), the SN was the only positive node. In another 9 cases (45%), patients had fewer than 4 positive axillary lymph nodes; more than 4 axillary nodes were metastatic in 2 cases (10%). Among the 28 patients with SN micrometastasis, 21 received complete axillary dissection: 15 patients (53.6%) had no other metastasis to the axillary nodes and 6 patients (21.4%) had cancer cells in other axillary nodes. In case of micrometastasis, we suggested that patients enter the International Breast Cancer Study Group 2301 trial (15 of them accepted and signed the informed consent), which compared completion of axillary dissection with no further surgical treatment of the axilla. Based on randomization, 7 patients (25%) in the group with micrometastasis to the SN received no axillary dissection. Patients' tolerance to this kind of treatment was excellent. CONCLUSION: Our experience indicates that SN biopsy performed with local anesthesia can be a suitable alternative to standard intraoperative evaluation with general anesthesia in patients with unifocal, early-stage breast carcinoma.

Sentinel Node Biopsy Interpretation: The Milan Experience.

From March 1996 to December 1999 we performed 1,266 sentinel node biopsies (SNBs) in patients with small breast cancers. The technique is to inject technetium 99m-labeled albumin particles close to the tumor, locate the sentinel node (SN) scintigraphically, and use a handheld gamma-detecting probe to guide its removal via a small incision during breast surgery. Our experience was divided into three phases. In the first phase, complete axillary dissection was performed to assess the accuracy of SNB in predicting axillary status. We also assessed safety, perfected tracer injection technique, determined optimal particle size and radioactivity levels, optimized lymphoscintigraphic scanning, and perfected the surgical technique. The SN was identified and removed in 98.7% of cases. Comparison with complete axillary dissection showed that the SN predicted axillary status in 96.8% of cases. However, use of an intraoperative frozen section method predicted axillary status in only 86.5% of cases. In the second phase we developed a new method for intraoperative histologic analysis. Extensive sampling (up to 60 sections/SN) and an experienced pathologist proved more important than use of antikeratin immunostaining in identifying tumor cells, and the new method has the accuracy of a definitive histologic examination. The third phase, a randomized trial, closed at the end of 1999. Trial objectives were to confirm that the SN predicts axillary status, to determine the number of axillary relapses, and to assess overall and disease-free survival. Patients were randomized in the operating room to complete axillary dissection or SNB. If the SN was positive, complete axillary dissection was performed; if the SN was negative, no further axillary treatment was given. We expect the trial to confirm our clinical experience that SNB is a safe and accurate procedure for staging patients with early breast cancer and a clinically negative axilla.