De-Escalation Surgery in cT3-4 Breast Cancer Patients after Neoadjuvant Therapy: Predictors of Breast Conservation and Comparison of Long-Term Oncological Outcomes with Mastectomy.

BACKGROUND: Neoadjuvant therapy (NAT) has become increasingly employed for the treatment of cT3-4 breast cancer (BC), enabling breast-conserving surgery (BCS) in cases traditionally considered for mastectomy. This study aims to identify predictors for breast conservation post-NAT and to evaluate whether BCS influences long-term oncological outcomes. METHODS: We retrospectively analyzed data from patients with cT3-4 BC who received NAT at the Breast Unit of IRCCS Humanitas Research Hospital, Milan, Italy, from October 2009 to April 2020. Surgical outcomes and long-term oncological results, such as disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), and BC-specific survival (BCSS), were compared between the BCS and mastectomy groups. RESULTS: Among 114 patients analyzed, 37 (32.5%) underwent BCS, and 77 (67.5%) had a mastectomy. The key predictors for opting for BCS included absence of vascular invasion, reduced tumor size post-NAT, and achieving ypT0 status. No significant differences in DFS, DDFS, OS, and BCSS were observed between the two surgical groups (log-ranks, p = 0.520, p = 0.789, p = 0.216, p = 0.559, respectively). CONCLUSIONS: BCS after NAT is a feasible and safe option for patients with cT3-4 BC, without adversely affecting long-term oncological outcomes. Identifying predictors of breast conservation can guide surgical decision-making, ensuring that patients receive optimal treatment.

Comparison of Long-Term Oncological Results in Young Women with Breast Cancer between BRCA-Mutation Carriers Versus Non-Carriers: How Tumor and Genetic Risk Factors Influence the Clinical Prognosis.

BACKGROUND: Breast cancer (BC) is very uncommon in young women (YW) and it is unclear whether a BRCA mutation has prognostic implications. Our aim was to evaluate the characteristics of YW with BC by comparing the long-term oncological results between BRCA-mutation carriers and non-carriers. METHODS: We retrospectively reviewed all the consecutive YW (aged 18-40 years) diagnosed with BC. Endpoints were disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: 63 YW with a BRCA mutation were compared with 339 YW without BRCA mutation. BRCA-mutation carriers were younger (60.3% versus 34.8% if age ≤ 35 years, p = 0.001) and presented with more aggressive tumors (66.7% versus 40.7% if G3, p = 0.001; 57.2% versus 12.4% if biological subtype triple-negative, p = 0.001; 73.0% versus 39.2% if Ki67 ≥ 25%, p = 0.001). Non-carriers presented significantly better DFS, DDFS, and OS compared with BRCA-mutation carriers. Neoadjuvant chemotherapy was found to be an independent protective factor for OS in BRCA-mutation carriers. CONCLUSIONS: BC is more likely to present at a younger age (≤ 35 years) and with more aggressive characteristics (G3, triple-negative, Ki67 ≥ 25%) in YW with BRCA mutation compared with their non-mutated counterparts. Young BRCA-mutation carriers showed a poorer prognosis in terms of recurrence and survival compared with non-carriers. The implementation of neoadjuvant chemotherapy may improve survival in YW with BC and BRCA mutation.

Sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer patients undergoing mastectomy with one to two metastatic sentinel lymph nodes: sub-analysis of the SINODAR-ONE multicentre randomized clinical trial and reopening of enrolment.

BACKGROUND: The initial results of the SINODAR-ONE randomized clinical trial reported that patients with T1-2 breast cancer and one to two macrometastatic sentinel lymph nodes treated with breast-conserving surgery, sentinel lymph node biopsy only, and adjuvant therapy did not present worse 3-year survival, regional recurrence, or distant recurrence rates compared with those treated with axillary lymph node dissection. To extend the recommendation of axillary lymph node dissection omission even in patients treated with mastectomy, a sub-analysis of the SINODAR-ONE trial is presented here. METHODS: Patients with T1-2 breast cancer and no more than two metastatic sentinel lymph nodes undergoing mastectomy were analysed. After sentinel lymph node biopsy, patients were randomly assigned to receive either axillary lymph node dissection followed by adjuvant treatment (standard arm) or adjuvant treatment alone (experimental arm). The primary endpoint was overall survival. The secondary endpoint was recurrence-free survival. RESULTS: A total of 218 patients were treated with mastectomy; 111 were randomly assigned to the axillary lymph node dissection group and 107 to the sentinel lymph node biopsy-only group. At a median follow-up of 33.0 months, there were three deaths (two deaths in the axillary lymph node dissection group and one death in the sentinel lymph node biopsy-only group). There were five recurrences in each treatment arm. No axillary lymph node recurrence was observed. The 5-year overall survival rates were 97.8 and 98.7 per cent in the axillary lymph node dissection treatment arm and the sentinel lymph node biopsy-only treatment arm, respectively (P = 0.597). The 5-year recurrence-free survival rates were 95.7 and 94.1 per cent in the axillary lymph node dissection treatment arm and the sentinel lymph node biopsy treatment arm, respectively (P = 0.821). CONCLUSION: In patients with T1-2 breast cancer and one to two macrometastatic sentinel lymph nodes treated with mastectomy, the overall survival and recurrence-free survival rates of patients treated with sentinel lymph node biopsy only were not inferior to those treated with axillary lymph node dissection. To strengthen the conclusion of the trial, the enrolment of patients treated with mastectomy was reopened as a single-arm experimental study. REGISTRATION NUMBER: NCT05160324 (http://www.clinicaltrials.gov).

Preservation of Axillary Lymph Nodes Compared with Complete Dissection in T1-2 Breast Cancer Patients Presenting One or Two Metastatic Sentinel Lymph Nodes: The SINODAR-ONE Multicenter Randomized Clinical Trial.

BACKGROUND: The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1-2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse. METHODS: Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm). RESULTS: The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936). CONCLUSIONS: The 3-year survival and relapse rates of T1-2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND.

Correlation between outcome and extent of residual disease in the sentinel node after neoadjuvant chemotherapy in clinically fine-needle proven node-positive breast cancer patients.

BACKGROUND: Whether the extent of residual disease in the sentinel lymph node (SLN) after neoadjuvant chemotherapy (NAC) influences the prognosis in clinically node-positive breast cancer (BC) patients remains to be ascertained. METHODS: One hundred and thirty-four consecutive cN+/BC-patients received NAC followed by SLN biopsy and axillary lymph node dissection. Cumulative incidence of overall (OS) and disease-free (DFS) survival, BC-related recurrences and death from BC were assessed using the Kaplan-Meier method both in the whole patient population and according to the SLN status. The log rank test was used for comparisons between groups. RESULTS: The SLN was identified in 123/134 (91.8%) patients and was positive in 98/123 (79.7%) patients. Sixty-five of them (66.3%) had other axillary nodes involved. SLN sensitivity and false-negative rate were 88.0% and 2.0%, Median follow-up was 10.2 years. Ten-year cumulative incidence of axillary, breast and distant recurrences, and death from BC were 6.5%, 11.9%, 33.4% and 31.3%, respectively. Ten-year OS and DFS were 67.3% and 55.9%. When stratified by SLN status, 10-year cumulative incidence of BC-related and loco-regional events, and death from BC were similar between disease-free SLN and micrometastatic SLN subgroups (28.9% vs 30.2%, p = 0.954; 21.6% vs 13.4%, p = 0.840; 12.9 vs 24.5%, p=0.494). Likewise, 10-year OS and DFS were comparable (80.0% vs 75.5%, p=0.975 and 68.0% vs 69.8, p=0.836). Both OS and DFS were lower in patients presenting a macrometastatic SLN (60.2% and 47.5%). CONCLUSION: Outcome of patients with micrometastatic SLN was similar to that of patients with disease-free SLN, which was more favorable as compared to that of patients with macrometastatic SLN.

Evolution and time trends of nipple-sparing mastectomy: a single-center experience.

Nipple Sparing Mastectomy (NSM) requires the entire breast tissue to be removed, maintaining the nipple-areola complex, and represents nowadays the gold standard of the demolitive breast surgery. Although it represents the evolution of conservative breast surgery, NSM presents some limitations in the selection of women candidates for treatment, and still there are no real guidelines regarding its indications, but simply objective data to address the choice. How the breast surgery approach to demolitive and conservative surgery has changed over time? We evaluated throughout the years (from 2009 up to 2018) the time trend of NSM at our institution and analysed the main differences between patients undergone NSM and other mastectomies and/or breast conserving surgery in terms of cancer size, multicentricity and biological profile. We found 781 NSMs, 1261 other mastectomies and 5621 breast conservative surgeries. Among NSMs, 39.6% were reconstructed with tissue expander and 58.1% with definitive prosthesis. From 2009 to 2018 we found a general increase of NSM rate (from 21.3% of all mastectomies in 2009 to 67.3% in 2018) and a decrease of total mastectomies (from 78.7% of all mastectomies in 2009 to 32.7% in 2018). In line with the literature data, our data confirm that in the recent years NSM represents the gold standard for radical breast surgery. Undisputed in prophylaxis, NSM is continuously acquiring more support in being used as first line treatment for locally advanced disease.

NEONOD 2: Rationale and design of a multicenter non-inferiority trial to assess the effect of axillary surgery omission on the outcome of breast cancer patients presenting only micrometastasis in the sentinel lymph node after neoadjuvant chemotherapy.

Sentinel lymph node biopsy alone, without complete axillary lymph node dissection, is the standard treatment of the axilla nodal chain in early-stage breast cancer patients presenting a negative sentinel lymph node. The updated results of the IBCSG 23-01 randomized trial recently provided evidence that this approach could be extended to early-stage breast cancer patients presenting only micrometastasis in the sentinel lymph node. On the other hand, patients with large operable or locally advanced breast cancer and clinically positive lymph nodes currently receive neoadjuvant chemotherapy and sentinel lymph node biopsy, which is then followed by complete axillary node dissection if the sentinel lymph node till contains tumor residue, regardless of the extent of nodal disease. Assuming that patients presenting only a micrometastatic sentinel lymph node after neoadjuvant chemotherapy are clinically equivalent to the IBCSG 23-01 early-breast cancer patients with only micrometastatic sentinel node, then complete axillary dissection would be unneeded also in these subset of patients in the neoadjuvant setting. The multicenter uncontrolled non-inferiority trial NEONOD 2 we here present was designed to assess this hypothesis, i.e. whether or not omission of complete axillary nodal clearance worsens prognosis in patients with sentinel node resulting only micrometastatic after neoadjuvant chemotherapy.

Mucinous breast cancer: A narrative review of the literature and a retrospective tertiary single-centre analysis.

Mucinous carcinoma (MC) is a rare breast cancer characterized by the presence of large extracellular mucin amount. Two main subtypes can be distinguished: pure (PMC) and mixed (MMC). We conducted a retrospective MC analysis in our prospective maintained database, calculating disease-free survival (DFS) and 5-year overall survival (OS). We found a global 92.1% OS (higher in MMC group and statistically significative) and a DFS of 95.3% (higher in MMC group but not statistically significative).

SINODAR ONE, an ongoing randomized clinical trial to assess the role of axillary surgery in breast cancer patients with one or two macrometastatic sentinel nodes.

Sentinel lymph node biopsy alone is the current surgical axillary treatment for early-stage breast cancer patients with a negative sentinel lymph node (SLN). The possibility to omit axillary dissection also in presence of positive SLNs has been promoted by the American College of Surgeons Oncology Group (ASOCOG) Z0011 randomized trial. Several limitations and evidences of potential selection bias made this trial fairly controversial. Stronger evidence than currently available is needed on the safety of foregoing axillary dissection in well-defined populations of patients with positive SLNs. The Italian multicentre SINODAR ONE randomized trial here presented was designed with this aim.

Sentinel Lymph Node Biopsy Versus Axillary Dissection in Node-Negative Early-Stage Breast Cancer: 15-Year Follow-Up Update of a Randomized Clinical Trial.

BACKGROUND: Sentinel lymph node biopsy (SLNB) allows for staging of the axillary node status in early-stage breast cancer (BC) patients and avoiding complete axillary lymph node dissection (ALND) when the sentinel lymph node (SLN) is proven to be free of disease. In a previous randomized trial we compared SLNB followed by ALND (ALND arm) with SLNB followed by ALND only if the SLN presented metastasis (SLNB arm). At a mid-term of ≈ 6 years median follow-up, the two strategies appeared to ensure similar survival and locoregional control. We have revised these previous findings and update the results following a 15-year observation period. METHODS: Patients were randomly assigned to either the ALND or SLNB arm. The main endpoints were event-free survival (EFS), overall survival (OS), and axillary disease recurrence. EFS and OS were assessed using Kaplan-Meier analysis and the log-rank test. RESULTS: The ALND and SLNB arms included 115 and 110 patients, respectively. At 14.3 years median follow-up, 39 primary BC-related recurrences occurred, 22 (19 %) of which occurred in the ALND arm and 17 (16 %) occurred in the SLNB arm (p = 0.519). No axillary relapse developed in the SLNB arm, while two were observed in the ALND arm. OS (82.0 vs. 78.8 %) and EFS (72.8 vs. 72.9 %) were not statistically different between the ALND and SLNB arms (p = 0.502 and 0.953, respectively). CONCLUSIONS: SLNB is a safe and efficacious component of the surgical treatment of early-stage BC patients. In the long-term, SLNB is equivalent to ALND in terms of locoregional nodal disease control and survival in this subset of patients.

Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials.

BACKGROUND: The role of temporary ovarian suppression with gonadotropin-releasing hormone analogues (GnRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. We conducted a systematic review and meta-analysis of randomized trials evaluating the efficacy of GnRHa, given before and during chemotherapy, in the prevention of POF in premenopausal cancer patients. METHODS: Studies were retrieved by searching PubMed, Web of Knowledge database and the proceedings of major conferences. We calculated Odds Ratios (OR) and 95% confidence intervals (CIs) for POF from each trial and obtained pooled estimates through the random effects model as suggested by DerSimonian and Laird. RESULTS: Nine studies were included in the meta-analysis with 225 events of POF occurring in 765 analyzed patients. The pooled OR estimate indicates a highly significant reduction in the risk of POF (OR=0.43; 95% CI: 0.22-0.84; p=0.013) in patients receiving GnRHa. There was statistically significant heterogeneity among studies (I(2)=55.8%; p=0.012). There was no evidence of publication bias. Subgroups analyses showed that the protective effect of GnRHa against POF was similar in subgroups of patients defined by age and timing of POF assessment, while it was present in breast cancer but unclear in ovarian cancer and lymphoma patients. CONCLUSIONS: Our pooled analysis of randomized studies shows that the temporary ovarian suppression induced by GnRHa significantly reduces the risk of chemotherapy-induced POF in young cancer patients.

Flat epithelial atypia: comparison between 9-gauge and 11-gauge devices.

BACKGROUND: This study aimed to establish if women with a diagnosis of flat epithelial atypia (FEA) without residual microcalcifications at stereotactic vacuum-assisted breast biopsy (VABB) could be managed with mammographic follow-up (FU) instead of surgery and to compare 9-gauge and 11-gauge devices. PATIENTS AND METHODS: From October 2003 to January 2011, 2382 VABB procedures were performed (1373 with 11-gauge and 1009 with 9-gauge). We found 121 cases of pure FEA that were surgically treated: 57 with a 9-gauge device (group 1) and 64 with an 11-gauge device (group 2). The underestimation rate (UR) of malignancy for patients without and those with residual microcalcifications for each VABB device was calculated. Differences between groups were analyzed with the Fischer exact test. RESULTS: The overall UR of FEA was 4% (2 of 57) with the 9-gauge device and 8% (5 of 64) with the 11-gauge device. With a 9-gauge device, the UR for patients without residual microcalcifications was 0% (0 of 46), and the UR for patients with residual microcalcifications was 18% (2 of 11). With an 11-gauge device, the UR for patients without residual microcalcifications was 0% (0 of 39), the UR for patients with residual microcalcifications at post-biopsy mammograms was 16% (5 of 25). With a 9-gauge device, 80% (46 of 57) of patients did not have residual microcalcifications after VABB. With an 11-gauge device, 60% (39 of 64) of patients had no residual microcalcifications after VABB. Differences between the 9-gauge and 11-gauge devices were statistically significant (P < .05). CONCLUSION: Women with FEA without residual microcalcifications after VABB can be managed conservatively. Nine-gauge VABB is associated with a lower percentage of residual microcalcifications compared with an 11-gauge device, but it is safe to follow patients with FEA if all calcifications are removed with the core biopsy.

Breast implant infections after surgical reconstruction in patients with breast cancer: assessment of risk factors and pathogens over extended post-operative observation.

BACKGROUND: Infection is a severe potential complication of breast implant positioning in women with cancer. There still is some degree of uncertainty regarding optimal antibiotic prophylaxis regimens, infecting pathogens, and risk factors associated with infection during long-term followup of these patients. METHODS: We performed a systematic clinical review to assess infecting microorganisms and risk factors among patients undergoing reconstructive procedures for breast cancer between January 2005 and February 2007. A randomly selected group of infection-free patients treated over the same time span was considered as a control. RESULTS: Among 240 women undergoing implant procedures performed and followed up as outpatients, 16 patients with prosthetic infections were observed (infection rate 6.7%). Infection was recorded within six months from surgery in 94% of the cases, with an overall mean time to infection of 95 days. The time interval between surgery and infection did not support a diagnosis of hospital-acquired infection in most cases. Gram-negative microorganisms were identified in seven cases. A higher proportion of patients with implant infection underwent radiotherapy or chemotherapy after surgery for advanced tumors compared with the control patients without infection. CONCLUSIONS: Extended post-operative surveillance is indicated, at least for the first six months after breast implant placement, particularly for women who need radiotherapy or chemotherapy after implant surgery. Gram-negative bacilli may be involved more often in late infections than otherwise expected. This finding may influence initial empiric antibiotic treatment.

Accelerated partial breast irradiation via the mammosite catheter: preliminary reports of a single-institution experience.

Several studies have shown that the majority of in-breast recurrences following lumpectomy are at or near the original tumor site while ipsilateral breast recurrences further a field occur rarely. This suggests that the radiation dose could be delivered exclusively to the tumor bed, allowing larger fractions to be used without increasing toxicity and shortening the total treatment time. We investigated the use of the MammoSite irradiation system with a view to analyzing complications, cosmesis and patient comfort. Between 2004 and 2007 intracavity brachytherapy was given to 30 patients using the MammoSite device. The reference isodose was prescribed to the lumpectomy cavity with a 1 cm margin. Geometric parameters and anatomic position of the applicator after implantation were checked via CT, x-ray and ultrasound. Analysis was done for patient quality of life, cosmesis, early and late complications. Forty-nine patients received a proposal for MammoSite brachytherapy. Nine declined, 40 enrolled while 10 were excluded for various reasons (Table 5). A total of 30 patients were actually treated to 34 Gy (2 x 3.4 Gy) in 5 days. We observed 3 cases (10%) of infection within 3 months of implantation. Symptomatic seroma was seen in five patients (16.6%) at 6 months, in three (10%) at 12 months, and in just one patient (3.3%) at 18 months. Good to excellent cosmetic results were achieved in 75% by patient and physician ratings. Accelerated partial breast irradiation using the MammoSite catheter produces favorable short-term outcomes, limited toxic effects on skin, and optimal cosmetic results. Patient tolerance for the treatment is very high. Critical issues may regard the importance of good cavity conformance and adequate balloon-skin distance in avoiding possible dose excesses to the skin. For a selected patient group, this could be a valid alternative to conventional whole breast irradiation.

Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.

BACKGROUND: To determine whether a dose-dense regimen improves outcome in early breast cancer patients, we compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14 including support with filgrastim, a granulocyte colony-stimulating factor) in a multicenter phase III randomized trial. METHODS: A total of 1214 patients with early-stage breast cancer were randomly assigned to receive six cycles of FEC14 (604 patients) or of FEC21 (610 patients). Study endpoints were overall survival and event-free survival. Associations were assessed by multivariable analysis with adjustment for age; tumor size; grade; proliferative rate; and menopausal, lymph node, estrogen receptor, and progesterone receptor status. All statistical tests were two-sided. RESULTS: Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation (26%) than those in the FEC21 arm (33%) (difference = 7%, 95% confidence interval [CI] = 2% to 12%; P = .008). FEC14 therapy, compared with FEC21 therapy, was associated with more asthenia (36% versus 29%, difference = 7%, 95% CI = 2% to 12%; P = .01), bone pain (33% versus 4%, difference = 29%, 95% CI = 25% to 33%; P < .001), anemia (38% versus 19%, difference = 19%, 95% CI = 14% to 24%; P < .001), and thrombocytopenia (8% versus 2%, difference = 6%, 95% CI = 4% to 9%; P < .001), but with less leukopenia (12% versus 45%, difference = 33%, 95% CI = 28% to 37%; P < .001). No acute myelogenous leukemia or myelodysplastic syndrome was observed. At a median follow-up of 10.4 years, no statistically significant difference in the hazard of death (hazard ratio [HR] = 0.87, 95% CI = 0.67 to 1.13) or recurrence (HR = 0.88, 95% CI = 0.71 to 1.08) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis. Although the study was underpowered for subset analysis, we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors. CONCLUSION: Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer. However, this therapy was not associated with improved outcome, but because of the limited statistical power of our study, we cannot rule out a modest improvement in outcome associated with FEC14 therapy.

Sentinel lymph node as a new marker for therapeutic planning in breast cancer patients.

BACKGROUND AND OBJECTIVES: Literature review suggests that the sentinel lymph node (sN) represents a reliable predictor of axillary lymph node status in breast cancer patients; however, some important issues, such as the optimisation of the technique for the intraoperative identification of the sN, the role of intraoperative frozen section examination of the sN, and the clinical implications of sN metastasis as regards the surgical management of the axilla, still require further confirmation. The authors aimed (1) to assess the feasibility of sN identification with a combined approach (vital blue dye lymphatic mapping and radioguided surgery, RGS) and the specific contribution of either techniques to the detection of the sN, (2) to determine the accuracy and usefulness of intraoperative frozen section examination of the sN in order to perform a one-stage surgical procedure, and (3) to define how the sN might modulate the therapeutic planning in different stages of disease. MATERIALS AND METHODS: From October 1997 to June 2001, 334 patients with early-stage (T(1-2) N(0) M(0)) invasive mammary carcinoma underwent sN biopsy; the average age of patients was 61.5 years (range, 39-75 years). In a subset of 153 patients, both vital blue dye (Patent Blue-V) lymphatic mapping and RGS were used to identify the sN, and the relative contribution of each of the two techniques was assessed. RESULTS: In the whole group, the sN was identified in 326 of 334 patients (97.6%), and 105 of 326 patients (37.3%) had positive axillary lymph nodes (pN+). In 9 of 105 pN+ patients, the definitive histologic examination of the sN did not show metastases but these were detected in non-sN, thus giving an 8.6% false-negative rate, a negative predictive value of 94.5% (156/165), and an accuracy of 96.5% (252/261). As regards the specific contribution of the two different techniques used in the identification of the sN, the detection rate was 73.8% (113/153) with Patent Blue-V alone, 94.1% (144/153) with RGS alone, and 98.7% (151/153) with Patent Blue-V combined with RGS (P < 0.001). Noteworthy, whenever the sN was identified, the prediction of axillary lymph node status was remarkably similar (93-95% sensitivity; 100% specificity; 95-97% negative predictive value, and 97-98% accuracy) whichever of the three procedures was adopted (Patent Blue-V alone, RGS alone, or combined Patent Blue-V and RGS). Intraoperative frozen section examination was performed in 261 patients, who had at least one sN identified, out of 267 patients who underwent complete axillary dissection; 170 patients had histologically negative sN (i.o. sN-) and 91 patients histologically positive sN (i.o. sN+). All 91 i.o. sN+ were confirmed by definitive histology, whereas in 14 of 170 i.o. sN- patients (8.2%) metastases were detected at definitive histology. As regards the correlation between the size of sN metastasis, the primary tumour size, and the status of non-sN in the axilla, micrometastases were detected at final histology in 23 patients and macrometastases in 82 patients. When only micrometastases were detected, the sN was the exclusive site of nodal metastasis in 20 of 23 patients (86.9%) while in 3 patients with tumour size larger than 10 mm micrometastases were detected also in non-sN. Macrometastases were never detected in pT(1a) breast cancer patients; the sN was the exclusive site of these metastases in 30 patients (36.6%), while in 52 patients (63.4%) there were metastases both in sN and non-sN. CONCLUSIONS: Sentinel lymphadenectomy can better be accomplished when both procedures (lymphatic mapping with vital blue dye and RGS) are used, because of the significantly higher sN detection rate, although the prediction of axillary lymph node status remains remarkably similar whichever method is used. The intraoperative frozen section examination proved to be rather accurate in predicting the actual pathologic status of the sN, with a negative predictive value of 91.8%; in 35% of patients it allowed sN biopsy and axillary dissection to be performed in a one-stage surgical procedure. Finally, specific clinical and histopathologic features of the primary tumour and sN might be used to tailor the loco-regional and systemic treatment in different clinical settings, such as in ductal carcinoma in-situ (DCIS), early-stage invasive breast cancer, and patients with large breast cancer undergoing neo-adjuvant CT for breast-saving surgery as well as elderly patients with operable breast cancer.

Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa.

Previous in vitro and in vivo studies showed a synergistic effect of concomitant doxorubicin and radiotherapy in a variety of solid tumors. From 1988 to 2000, we have investigated in a pilot study and then in a phase II study the efficacy of a concomitant doxorubicin radiotherapy treatment in patients with advanced and/or metastatic soft tissue sarcomas (STS). We enrolled and treated a group of 115 patients with advanced STS, with metastases (61%), frequently pretreated (59%), predominantly G2/G3 (84%). Doxorubicin was administered by continuous infusion at a dose of 12 mg/m(2)/day over 5 consecutive days concomitantly with radiotherapy; treatment was given on ambulatory basis at 2-week intervals with support of granulocytes colony stimulating factors (GCSF). In the whole group of 115 patients a clinical objective response (ORs) rate of 67% was obtained, with 11% complete and 56% partial responses. No patient progressed while on therapy, except one who progressed in non-irradiated metastatic tumor. Treatment (median 3 cycles) was well tolerated with no WHO grade 3 toxicity (apart from alopecia) and no acute or chronic cardiotoxicity. Thirty-nine responder patients underwent surgery (24 primary tumors, 10 relapses, 5 relapses plus isolated lung metastases). The median survival time(s) was 29 months in the whole series and over 50 months in responder patients. A multivariate analysis showed a positive association between survival and sex (HR=1.8; CI 95%, 1.0-3.4), performance status (HR=2.1; CI 95%, 1.1-4.0), ORs (HR=7.9; CI 95%, 3.5-18.1) and surgery (HR=8.8; CI 95%, 2.1-35.9). Low toxicity, high OR rate and positive survival time trend make the concomitant chemo-radiotherapy an efficacious approach for advanced STS.