Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial.

BACKGROUND: Intraoperative radiotherapy with electrons allows the substitution of conventional postoperative whole breast irradiation with one session of radiotherapy with the same equivalent dose during surgery. However, its ability to control for recurrence of local disease required confirmation in a randomised controlled trial. METHODS: This study was done at the European Institute of Oncology (Milan, Italy). Women aged 48-75 years with early breast cancer, a maximum tumour diameter of up to 2·5 cm, and suitable for breast-conserving surgery were randomly assigned in a 1:1 ratio (using a random permuted block design, stratified for clinical tumour size [<1·0 cm vs 1·0-1·4 cm vs ≥1·5 cm]) to receive either whole-breast external radiotherapy or intraoperative radiotherapy with electrons. Study coordinators, clinicians, and patients were aware of the assignment. Patients in the intraoperative radiotherapy group received one dose of 21 Gy to the tumour bed during surgery. Those in the external radiotherapy group received 50 Gy in 25 fractions of 2 Gy, followed by a boost of 10 Gy in five fractions. This was an equivalence trial; the prespecified equivalence margin was local recurrence of 7·5% in the intraoperative radiotherapy group. The primary endpoint was occurrence of ipsilateral breast tumour recurrences (IBTR); overall survival was a secondary outcome. The main analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01849133. FINDINGS: 1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007. After a medium follow-up of 5·8 years (IQR 4·1-7·7), 35 patients in the intraoperative radiotherapy group and four patients in the external radiotherapy group had had an IBTR (p<0·0001). The 5-year event rate for IBRT was 4·4% (95% CI 2·7-6·1) in the intraoperative radiotherapy group and 0·4% (0·0-1·0) in the external radiotherapy group (hazard ratio 9·3 [95% CI 3·3-26·3]). During the same period, 34 women allocated to intraoperative radiotherapy and 31 to external radiotherapy died (p=0·59). 5-year overall survival was 96·8% (95% CI 95·3-98·3) in the intraoperative radiotherapy group and 96·9% (95·5-98·3) in the external radiotherapy group. In patients with data available (n=464 for intraoperative radiotherapy; n=412 for external radiotherapy) we noted significantly fewer skin side-effects in women in the intraoperative radiotherapy group than in those in the external radiotherapy group (p=0·0002). INTERPRETATION: Although the rate of IBTR in the intraoperative radiotherapy group was within the prespecified equivalence margin, the rate was significantly greater than with external radiotherapy, and overall survival did not differ between groups. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons. FUNDING: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, and Umberto Veronesi Foundation.

Repeating conservative surgery after ipsilateral breast tumor reappearance: criteria for selecting the best candidates.

BACKGROUND: Mastectomy is still considered the treatment of first choice in patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and whole-breast radiotherapy. METHODS: We retrospectively evaluated 161 patients with invasive IBTR who underwent a second BCS in order to describe prognosis, determine predictive factors of outcome, and select the subset of patients with the best local control. Median follow-up after IBTR was 81 months. RESULTS: Median age at IBTR was 53 years. Five-year overall survival after IBTR was 84 % (95 % confidence interval [CI] 78-89). Five-year cumulative incidence of a second local event after IBTR was 29 % (95 % CI 22-37). At the multivariate analysis, IBTR size >2 cm and time to relapse ≤48 months significantly increased the risk of local reappearance (hazard ratio [HR] 3.3, 95 % CI 1.6-7.0; and HR 1.9, 95 % CI 1.1-3.5). The 5-year cumulative incidence of a further local reappearance of the tumor after repeating BCS was 15.2 % in the patients with IBTR ≤2 cm and time to IBTR >48 months, 31.2 % in the patients with IBTR ≤2 cm and time to IBTR ≤48 months, and 71.2 % in patients with IBTR >2 cm (P < 0.001). CONCLUSIONS: The best candidates for a second BCS are those with small (≤2 cm) and late (>48 months) IBTR. The information about the risk of a further local reappearance after repeating BCS should be shared with the patients in the decision making process.

Corrigendum: Results of the ECHO (Eating habits CHanges in Oncologic patients) Survey: An Italian Cross-Sectional Multicentric Study to Explore Dietary Changes and Dietary Supplement Use, in Breast Cancer Survivors.

[This corrects the article DOI: 10.3389/fonc.2021.705927.].

Results of the ECHO (Eating habits CHanges in Oncologic patients) Survey: An Italian Cross-Sectional Multicentric Study to Explore Dietary Changes and Dietary Supplement Use, in Breast Cancer Survivors.

The role of a healthy diet in cancer prevention is well recognized. Recent data indicate that following the same advices can also improve cancer survivors' quality of life. Breast cancer (BC) patients are commonly concerned about diet and nutrition and frequently express the need to obtain health-related information and the will to change their diet and lifestyle. Hence, be aware of survivors' dietary changes and information needs is crucial for healthcare professionals to guide them toward optimal lifestyle choices. In order to investigate eating habits changes in a BC survivors' population, we conceived the cross-sectional multicentric study ECHO (Eating habits CHanges in Oncologic patients) Survey. Data were collected from 684 patients, diagnosed with invasive breast cancer, in order to investigate their changes in food consumption, use of supplements, or the beginning of a specific diet, after BC diagnosis. We also examined the sources of information used and if any modification in their diets was reported to the oncologist. We primarily observed that patients increased their consumption of vegetables, pulses, nuts, fruits, wholemeal bread/pasta, grains and fish; while decreasing red and processed meat, refined bread/pasta, baked good and animal fat consumption. Survivors also reported the use of dietary supplements, mainly vitamins, aimed at counteracting therapies' side effects. Changes in nutritional habits were often adopted without asking or informing the oncologist. Despite BC survivors made some positive changes in their nutritional habits, those modifications were mostly pursued by less than half of them, while the majority of patients consumed nutritional supplements after diagnosis. These results, as well as the failure to communicate with the physicians, reinforce the need to both improve the patient-healthcare professional relationship and to develop tailored nutrition counselling and intervention programs for cancer survivors.

Tailored axillary surgery with or without axillary lymph node dissection followed by radiotherapy in patients with clinically node-positive breast cancer (TAXIS): study protocol for a multicenter, randomized phase-III trial.

BACKGROUND: Complete lymph node removal through conventional axillary dissection (ALND) has been standard treatment for breast cancer patients for almost a century. In the 1990s, however, and in parallel with the advent of the sentinel lymph node (SLN) procedure, ALND came under increasing scrutiny due to its association with significant patient morbidity. Several studies have since provided evidence to suggest omission of ALND, often in favor of axillary radiation, in selected clinically node-negative, SLN-positive patients, thus supporting the current trend in clinical practice. Clinically node-positive patients, by contrast, continue to undergo ALND in many cases, if only for the lack of studies re-assessing the indication for ALND in these patients. Hence, there is a need for a clinical trial to evaluate the optimal treatment for clinically node-positive breast cancer patients in terms of surgery and radiotherapy. The TAXIS trial is designed to fill this gap by examining in particular the value of tailored axillary surgery (TAS), a new technique for selectively removing positive lymph nodes. METHODS: In this international, multicenter, phase-III, non-inferiority, randomized controlled trial (RCT), including 34 study sites from four different countries, we plan to randomize 1500 patients to either receive TAS followed by ALND and regional nodal irradiation excluding the dissected axilla, or receive TAS followed by regional nodal irradiation including the full axilla. All patients undergo adjuvant whole-breast irradiation after breast-conserving surgery and chest-wall irradiation after mastectomy. The main objective of the trial is to test the hypothesis that treatment with TAS and axillary radiotherapy is non-inferior to ALND in terms of disease-free survival of clinically node-positive breast cancer patients in the era of effective systemic therapy and extended regional nodal irradiation. The trial was activated on 31 July 2018 and the first patient was randomized on 7 August 2018. DISCUSSION: Designed to test the hypothesis that TAS is non-inferior to ALND in terms of curing patients and preventing recurrences, yet is significantly superior in reducing patient morbidity, this trial may establish a new worldwide treatment standard in breast cancer surgery. If found to be non-inferior to standard treatment, TAS may significantly contribute to reduce morbidity in breast cancer patients by avoiding surgical overtreatment. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03513614. Registered on 1 May 2018. www.kofam.ch , ID: NCT03513614 . Registered on 17 June 2018. EudraCT No.: 2018-000372-14.

The evolution of the conservative approach to breast cancer.

The profound revolution that surgical treatment of breast cancer has undergone during the past 30 years has led to the progressive reduction of the extent of surgery, with less mutilation. As a consequence, quality of life has improved and women are now more motivated to follow screening programs for early diagnosis of the disease. Since conservative surgery is as effective as radical surgery, research is now focused on reducing radiotherapy. Overall, survival after breast cancer is not affected by reducing the extent of surgery, which, together with less invasive diagnostic procedures, has a good effect on patients' quality of life. For this reason in our Institute we are now evaluating the feasibility of a reduction of the radiation field and the sensibility and sensitivity of new diagnostic approaches for axillary staging.

Feasibility of lymphoscintigraphy for sentinel node identification after neo-adjuvant therapy.

AIM: To assess the sentinel-node identification rate at lymphoscintigraphy and its technical feasibility after neo-adjuvant treatments. MATERIAL OF STUDY: Between 2000 and 2013, 444 consecutive patients affected by primary locally advanced breast cancer were enrolled in this study. All individuals were candidate for neo-adjuvant treatments and for lymphoscintigraphy before surgery. RESULTS: The median age was 44 years at onset; almost one sentinel node was identified during lymphoscintigraphy in 430 cases. The detection rate at lymphoscintigraphy was 96.9% (95% CI, 94.8-98.1%). Considering the correlation between specific treatments and sentinel node identification rate, we verified that the detection rate did not vary significantly (p=0.53) according to the type of neo-adjuvant therapies administered to the patients. CONCLUSIONS: Our results demonstrated that lymphoscintigraphy for sentinel node identification is a safe and feasible procedure after neo-adjuvant therapies, independently of treatment types. KEY WORDS: Breast Cancer, Neo-Adjuvant Treatment, Sentinel lymphnode biopsy, Lymphoscintigraphy.

Surgical treatment of breast lesions at a Day Centre: Experience of the European Institute of Oncology.

Breast cancer is the commonest malignancy in women worldwide. The reduced aggressiveness of breast cancer surgery has made it possible treat patients in the day surgery setting. The European Institute of Oncology, Milan, opened its new Day Center in May 2010. From May 2010 to December 2014, 17,087 patients with breast conditions were treated by the Institute's Division of Senology, 4132 (24.2%) of these in the day surgery setting, including malignant and benign conditions; 204 (4.9%) were not discharged on the day of surgery, being converted to inpatients; five (0.1%) patients returned to hospital for persistent hematoma. Our experience of performing breast cancer surgery in the day surgery setting is in line that of the literature. It is safe, but requires a well-organized unit and multidisciplinary medical team to function smoothly, with much attention paid to patient comfort and education, so as to ensure maximum patient acceptance and satisfaction.

Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2.

PURPOSE: To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity. EXPERIMENTAL DESIGN: A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies. RESULT: Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity. CONCLUSIONS: The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.

Breast conservative surgery for well-differentiated ductal intraepithelial neoplasia: Risk factors for ipsilateral breast tumor recurrence.

RATIONAL: We retrospectively analyzed 232 patients affected by well differentiated ductal intraepithelial neoplasia (DIN1c or DCIS G1) treated with conservative surgery without adjuvant radiotherapy. RESULTS: 25 invasive and 18 non-invasive local recurrences were observed (median follow-up 80 months; 5-year cumulative incidence: 12.2%). Seven of the 15 young patients (<40 y) developed local recurrence (2 in situ, 5 invasive). Age <50 (HR 1.89, 95% C.I. 1.01-3.45), multifocality (HR 3.21, 95% C.I. 1.46-7.06), Ki-67 > 7% (HR 2.33, 95% C.I. 1.20-4.55) and surgical margins <10 mm (HR 2.00, 95% C.I. 1.06-3.76) were significantly associated with an increased risk of local recurrence. CONCLUSIONS: Young age, multifocality and small margins appeared as clear risk factors of local recurrence in DIN1c (DCIS G1) population. The presence of multiple poor prognostic features warrant a thorough discussion regarding local treatment.

Immediate breast reconstruction after mastectomy.

AIMS: There is a general agreement for immediate breast reconstruction in case of in situ tumors, while the reconstruction is often still delayed in cases of invasive cancers or not performed in the elderly cohort. Aim of this review is to investigate the safety of immediate postmastectomy reconstruction for invasive cancers and in the elderly population. METHODS AND RESULTS: We reviewed our series and the recent literature on this topic. While there is a general consensus that advanced age is not a contraindication to immediate reconstruction and breast reconstruction can be successfully performed on well-selected elderly patients, many oncologists in Europe do not prefer immediate reconstruction for invasive carcinoma, advocating the risk of delay of the medical adjuvant treatment in case of complications due to the reconstructive procedure. Our experience and a lot of studies suggest that immediate breast reconstruction is a safe and reliable treatment option in case of invasive cancers. However, if postmastectomy irradiation is necessary on the basis of the final pathological finding, this is associated with a high rate of surgical complications and implant loss among patients who underwent immediate reconstruction with prostheses. Moreover, current evidence suggests that postmastectomy radiation therapy also adversely affects autologous tissue reconstruction. CONCLUSIONS: Immediate breast reconstruction after mastectomy is an integral part of the complete management of breast cancer. Determining the risk of postmastectomy irradiation prior to definitive resection and reconstructive operations may reduce complications and improve aesthetic outcomes by guiding surgical decision making.

Axillary radiotherapy instead of axillary dissection: a randomized trial. Italian Oncological Senology Group.

BACKGROUND: Surgical dissection of the axilla is a standard part of the treatment of breast cancer but, by itself, does not improve prognosis; furthermore, most patients with small-sized breast cancer and a clinically uninvolved axilla never develop axillary metastases. We evaluated disease-free and overall survival in patients with early breast cancer treated by breast-conservation surgery without dissection of axillary lymph nodes, receiving or not receiving axillary radiotherapy (RT). METHODS: From 1995 to 1998, 435 patients older than 45 years with breast cancer up to 1.2 cm were randomized, 214 to breast conservation without axillary treatment and 221 to breast conservation plus axillary RT. RESULTS: After a follow-up of 28 to 68 months (median, 42 months), two women (1%) in the no axillary treatment group and one (.5%) in the axillary RT group developed axillary metastases. Rates of distant metastases and local treatment failure were also very low, and 5-year overall survival was 99%. CONCLUSIONS: After a mean of 46 months of follow-up, our results indicate that axillary dissection can be safely avoided in patients with very small invasive carcinomas and a clinically negative axilla. Whether axillary RT should be added can be assessed only by longer follow-up.