A comparison of frailty measures in population-based data for patients with colorectal cancer.

BACKGROUND: Numerous studies have revealed age-related inequalities in colorectal cancer care. Increasing levels of frailty in an ageing population may be contributing to this, but quantifying frailty in population-based studies is challenging. OBJECTIVE: To assess the feasibility, validity and reliability of the Hospital Frailty Risk Score (HFRS), the Secondary Care Administrative Records Frailty (SCARF) index and the frailty syndromes (FS) measures in a national colorectal cancer cohort. DESIGN: Retrospective population-based study using 136,008 patients with colorectal cancer treated within the English National Health Service. METHODS: Each measure was generated in the dataset to assess their feasibility. The diagnostic codes used in each measure were compared with those in the Charlson Comorbidity Index (CCI). Validity was assessed using the prevalence of frailty and relationship with 1-year survival. The Brier score and the c-statistic were used to assess performance and discriminative ability of models with included each measure. RESULTS: All measures demonstrated feasibility, validity and reliability. Diagnostic codes used in SCARF and CCI have considerable overlap. Prevalence of frailty determined by each differed; SCARF allocating 55.4% of the population to the lowest risk group compared with 85.1% (HFRS) and 81.2% (FS). HFRS and FS demonstrated the greatest difference in 1-year overall survival between those with the lowest and highest measured levels of frailty. Differences in model performance were marginal. CONCLUSIONS: HFRS, SCARF and FS all have value in quantifying frailty in routine administrative health care datasets. The most suitable measure will depend on the context and requirements of each individual epidemiological study.

Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients.

Postoperative delirium (POD) remains a common, dangerous and resource-consuming adverse event but is often preventable. The whole peri-operative team can play a key role in its management. This update to the 2017 ESAIC Guideline on the prevention of POD is evidence-based and consensus-based and considers the literature between 01 April 2015, and 28 February 2022. The search terms of the broad literature search were identical to those used in the first version of the guideline published in 2017. POD was defined in accordance with the DSM-5 criteria. POD had to be measured with a validated POD screening tool, at least once per day for at least 3 days starting in the recovery room or postanaesthesia care unit on the day of surgery or, at latest, on postoperative day 1. Recent literature confirmed the pathogenic role of surgery-induced inflammation, and this concept reinforces the positive role of multicomponent strategies aimed to reduce the surgical stress response. Although some putative precipitating risk factors are not modifiable (length of surgery, surgical site), others (such as depth of anaesthesia, appropriate analgesia and haemodynamic stability) are under the control of the anaesthesiologists. Multicomponent preoperative, intra-operative and postoperative preventive measures showed potential to reduce the incidence and duration of POD, confirming the pivotal role of a comprehensive and team-based approach to improve patients' clinical and functional status.

Clinical evaluation of molecular surrogate subtypes in patients with ipsilateral multifocal primary breast cancer.

BACKGROUND: When ipsilateral multifocal primary breast cancer (IMBC) is detected, standard routine is to evaluate the largest tumor with immunohistochemistry (IHC). As all foci are not routinely characterized, many patients may not receive optimal adjuvant treatment. Here, we assess the clinical relevance of examining at least two foci present in patients with IMBC. METHODS: Patients diagnosed and treated for IMBC at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2012 and 2017 were screened. In total, 180 patients with ≥ 2 invasive foci (183 specimens) were assessed with IHC and included in this study. Expression of the estrogen (ER) and progesterone (PR) receptors, Ki67, HER2, and tumor grade were used to determine the molecular surrogate subtypes and discordance among the foci was recorded. An additional multidisciplinary team board was then held to re-assess whether treatment recommendations changed due to discordances in molecular surrogate subtype between the different foci. RESULTS: Discordance in ER, PR, HER2, and Ki67 was found in 2.7%, 19.1%, 7.7%, and 16.9% of invasive foci, respectively. Discordance in the molecular surrogate subtypes was found in 48 of 180 (26.7%) patients, which resulted in therapy changes for 11 patients (6.1%). These patients received additional endocrine therapy (n = 2), chemotherapy (n = 3), and combined chemotherapy and trastuzumab (n = 6). CONCLUSION: Taken together, when assessing at least two tumor foci with IHC, regardless of shared morphology or tumor grade between the different foci, 6.1% of patients with IMBC were recommended additional adjuvant treatment. A pathologic assessment using IHC of all foci is therefore recommended to assist in individualized treatment decision making.

Health-Related Quality of Life After Nipple-Sparing Mastectomy: Results From the INSPIRE Registry.

INTRODUCTION: Nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) is increasingly used for both breast cancer (TNSM) and risk reduction (RRNSM). The aim of the study is to report the results of the INSPIRE registry assessing health-related quality of life (HRQoL) comparing baseline and 1-year follow-up, regarding surgical indications and chemotherapy (CT) received. METHODS: INSPIRE is a prospective database including women undergoing NSM and IBR from 18 countries. HRQoL was measured using EORTC QLQC30 and QLQ-BR23 before surgery and after 1 year. RESULTS: A total of 677 women were included, of whom 537 (79.3%) underwent TNSM and 140 (21.6%) RRNSM: in total, 806 NSM (556 TNSM and 250 RRNSM). Nipple involvement was present in 7.73% of TNSM and incidental carcinoma in 1.2% of the RRNSM group. Out of the overall 537 patients with systemic treatment, 177 (32.96%) received neoadjuvant chemotherapy (NCT) and 118 (21.92%) adjuvant chemotherapy (CT). A total of 227 patients (28.16%) developed at least one complication postoperatively, 164 (29.5%) in the TNSM group and 63 (25.2%) in the RRNSM group. The TNSM group improved in global health status and emotional functioning after 1 year. No differences were found when comparing HRQoL at 1 year between patients who received NCT and those who received adjuvant CT. The RRNSM group showed improvement in HRQoL, with better emotional functioning and fatigue after 1 year. CONCLUSIONS: This registry reports HRQoL findings after NSM. The impact of CT on worse HRQoL is independent from its timing. Patients with RRNSM showed an improved HRQoL at 1-year follow-up. Discussion of HRQoL outcomes with patients will facilitate the informed decision-making when considering NSM.

Timed up and go test and long-term survival in older adults after oncologic surgery.

BACKGROUND: Physical performance tests are a reflection of health in older adults. The Timed Up and Go test is an easy-to-administer tool measuring physical performance. In older adults undergoing oncologic surgery, an impaired TUG has been associated with higher rates of postoperative complications and increased short term mortality. The objective of this study is to investigate the association between physical performance and long term outcomes. METHODS: Patients aged ≥65 years undergoing surgery for solid tumors in three prospective cohort studies, 'PICNIC', 'PICNIC B-HAPPY' and 'PREOP', were included. The TUG was administered 2 weeks before surgery, a score of ≥12 seconds was considered to be impaired. Primary endpoint was 5-year survival, secondary endpoint was 30-day major complications. Survival proportions were estimated using Kaplan-Meier curves. Cox- and logistic regression analysis were used for survival and complications respectively. Hazard ratios (aHRs) and Odds ratios (aOR) were adjusted for literature-based and clinically relevant variables, and 95% confidence intervals (95% CIs) were estimated using multivariable models. RESULTS: In total, 528 patients were included into analysis. Mean age was 75 years (SD 5.98), in 123 (23.3%) patients, the TUG was impaired. Five-year survival proportions were 0.56 and 0.49 for patients with normal TUG and impaired TUG respectively. An impaired TUG was an independent predictor of increased 5-year mortality (aHR 1.43, 95% CI 1.02-2.02). The TUG was not a significant predictor of 30-day major complications (aOR 1.46, 95% CI 0.70-3.06). CONCLUSIONS: An impaired TUG is associated with increased 5-year mortality in older adults undergoing surgery for solid tumors. It requires further investigation whether an impaired TUG can be reversed and thus improve long-term outcomes. TRIAL REGISTRATION: The PICNIC studies are registered in the Dutch Clinical Trial database at www.trialregister.nl: NL4219 (2010-07-22) and NL4441 (2014-06-01). The PREOP study was registered with the Dutch trial registry at www.trialregister.nl: NL1497 (2008-11-28) and in the United Kingdom register (Research Ethics Committee reference 10/H1008/59).  https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/?page=15&query=preop&date_from=&date_to=&research_type=&rec_opinion=&relevance=true .

Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer.

BACKGROUND: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. METHODS: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. RESULTS: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed. CONCLUSIONS: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. TRIAL REGISTRATION: ISRCTN 46099296.

Comparison of breast cancer surrogate subtyping using a closed-system RT-qPCR breast cancer assay and immunohistochemistry on 100 core needle biopsies with matching surgical specimens.

BACKGROUND: Routine clinical management of breast cancer (BC) currently depends on surrogate subtypes according to estrogen- (ER) and progesterone (PR) receptor, Ki-67, and HER2-status. However, there has been growing demand for reduced immunohistochemistry (IHC) turnaround times. The Xpert® Breast Cancer STRAT4* Assay (STRAT4)*, a standardized test for ESR1/PGR/MKi67/ERBB2 mRNA biomarker assessment, takes less than 2 hours. Here, we compared the concordance between the STRAT4 and IHC/SISH, thereby evaluating the effect of method choice on surrogate subtype assessment and adjuvant treatment decisions. METHODS: In total, 100 formalin-fixed paraffin-embedded core needle biopsy (CNB) samples and matching surgical specimens for 98 patients with primary invasive BC were evaluated using the STRAT4 assay. The concordance between STRAT4 and IHC was calculated for individual markers for the CNB and surgical specimens. In addition, we investigated whether changes in surrogate BC subtyping based on the STRAT4 results would change adjuvant treatment recommendations. RESULTS: The overall percent agreement (OPA) between STRAT4 and IHC/SISH ranged between 76 and 99% for the different biomarkers. Concordance for all four biomarkers in the surgical specimens and CNBs was only 66 and 57%, respectively. In total, 74% of surgical specimens were concordant for subtype, regardless of the method used. IHC- and STRAT4-based subtyping for the surgical specimen were shown to be discordant for 25/98 patients and 18/25 patients would theoretically have been recommended a different adjuvant treatment, primarily receiving more chemotherapy and trastuzumab. CONCLUSIONS: A comparison of data from IHC/in situ hybridization and STRAT4 demonstrated that subsequent changes in surrogate subtyping for the surgical specimen may theoretically result in more adjuvant treatment given, primarily with chemotherapy and trastuzumab.

Considerations in Surgical Management of Gastrointestinal Cancer in Older Patients.

PURPOSE OF REVIEW: The goal of this manuscript is to present new and thought-provoking information related to the surgical care of older patients. We focused on four main areas including communication, surgical pathways, the care of emergency surgery patients, and functional recovery and quality of life. We sought to answer how these areas have evolved, affecting the care of older patients. RECENT FINDINGS: Older patients with cancer present particular challenges in relation to communication, goals, surgical treatment, and post-surgical outcomes. Communication should be clear early and during the treatment course. A multidisciplinary, multimodality, multi-phase pathway can be utilized to improve the postoperative outcomes of older patients with cancer. Functional recovery and quality of life can and should be measured in this population. Communication is complicated in cancer patients, which is made more complex with advancing age. Communication is the cornerstone of the treatment of older patients. Future research should focus on interventions to improve communication and measure quality of life and functional recovery metrics.

The Intricate Relationship between Melatonin and Breast Cancer: A Short Review.

Melatonin is a relatively recently isolated hormone, produced by the pineal gland. Its implication in several cell functions has augmented interest from scientists worldwide. There is ongoing research investigating the deterrent relationship between melatonin and malignancies and in particular breast cancer. The aim of this article is to review some of the most important findings concerning the effect of melatonin on cancer biology, from both preclinical and clinical studies providing an insight to the complex biological actions of this molecule, as well as their potential significance. The last part concentrates on the oncostatic activities of melatonin on breast cancer and special attention is given on the interplay between melatonin and estrogen. Epidemiological, experimental and clinical evidence indicates that this area is worth further investigation.

Addition of chemotherapy to local therapy in women aged 70 years or older with triple-negative breast cancer: a propensity-matched analysis.

BACKGROUND: There is a scarcity of data exploring the benefits of adjuvant or neoadjuvant chemotherapy in the treatment of breast cancer in older women. We aimed to explore the effect of adding chemotherapy to local therapy on overall survival in older women with triple-negative breast cancer. METHODS: For this propensity-matched analysis, we used data from the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. We included data from women aged 70 years or older with surgically treated, American Joint Committee on Cancer (AJCC) Stage I-III invasive triple-negative breast cancer diagnosed from 2004 to 2014. Patients with T1aN0M0 disease and those with incomplete data on oestrogen receptor status, progesterone receptor status, or HER2 status were excluded. To reduce bias, patients were subdivided into three groups: those who were recommended chemotherapy but did not receive it; those who received chemotherapy; and those for whom chemotherapy was not recommended and not given. The primary outcome was overall survival. Multivariate Cox regression analysis and propensity score matching were done to minimise bias. FINDINGS: Between Jan 1, 2004, and Dec, 31, 2014, 16 062 women with triple-negative breast cancer in the database met the inclusion criteria for this analysis. Median follow-up was 38·3 months (IQR 20·7-46·1, range 0-138·0; 95% CI 37·8-38·7). Collectively, the 5-year overall survival estimate of the 16 062 patients in the study cohort was 62·3% (95% CI 59·7-64·4). 5-year estimated overall survival was 68·5% (95% CI 66·4-70·6) for patients receiving chemotherapy, 61·1% (59·0-63·2) for patients recommended but not given chemotherapy, and 53·7% (51·8-55·8) for patients not recommended chemotherapy and not given chemotherapy (pooled log rank p<0·0001). Multivariate Cox regression analysis of a propensity score-matched sample comparing those who received chemotherapy with those who were recommended but not given chemotherapy (n=1884 matched pairs) identified improved overall survival with chemotherapy (hazard ratio [HR] 0·69 [95% CI 0·60-0·80]; p<0·0001). After stratifying the propensity score matching sample, this benefit persisted for node-negative women (HR 0·80 [95% CI 0·66-0·97]; p=0·007), node-positive women (0·76 [0·64-0·91]; p=0·006), and those with a comorbidity score greater than 0 (HR 0·74 [95% CI 0·59-0·94]; p=0·013). INTERPRETATION: These data support consideration of chemotherapy in the treatment of women aged 70 years or older with triple-negative breast cancer. FUNDING: None.

Surgical oncology in the elderly.

Poor cancer-specific outcomes in the elderly group are primarily a surgical failure. Surgeons are insufficiently trained to draw a line between fit and frail patients; this results in over-treatment of the frail patient, as well as under-treatment of the fit one. Communication skills should be improved to better understand the patient's requests. The timing of the surgical procedure is crucially important; all efforts should be put in place to optimize the patient's conditions before the surgery takes place.

Towards an evidence-informed value scale for surgical and radiation oncology: a multi-stakeholder perspective.

Surgery and radiotherapy, two locoregional cancer treatments, are essential to help improve cancer outcomes, control, and palliation. The continued evolution in treatment processes, techniques, and technologies-often at substantially increased costs-demands for direction on outcomes that are most valued by patients, and the evidence that is required before clinical adoption of these practices. Three recently introduced frameworks-the European Society for Medical Oncology Magnitude of Clinical Benefit Scale, the American Society of Clinical Oncology Value Framework, and the National Comprehensive Cancer Network Blocks-which all help define the value of oncology treatments, were appraised with a focus on their methods and definition of patient benefit. In this Review, we investigate the applicability of these frameworks to surgical and radiotherapy innovations. Findings show that these frameworks are not immediately transferable to locoregional cancer treatments. Moreover, the lack of emphasis on patient perspective and the reliance on traditional, trial-based endpoints such as survival, disease-free survival, and safety, calls for a new framework that includes real-world evidence with focus on the whole spectrum of patient-centred endpoints. Such an evidence-informed value scale would safeguard against the proliferation of low-value innovation while simultaneously increasing access to treatments that show significant improvements in the outcomes of cancer care.

Variation in treatment and survival of older patients with non-metastatic breast cancer in five European countries: a population-based cohort study from the EURECCA Breast Cancer Group.

BACKGROUND: Older patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival. METHODS: Population-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated. RESULTS: In total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30-6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium. CONCLUSIONS: There is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

Functional recovery and patient-reported outcomes after surgery.

This manuscript centers on what surgeons, patients, and hospital administrations want and need to know about the crucial role of functional recovery and patients' reported outcome measure, above all in the elderly population. From all angles, it is clear that elderly patients are unique and their cancer care should be individualized and approached in a multidisciplinary fashion. Evaluation of patient fitness to undergo surgery should be undertaken in the elective and emergent settings. If patients are deemed fit for treatment, they should be offered the appropriate treatment, regardless of their age. This includes proceeding with surgery and/or chemotherapy and utilizing minimally invasive techniques, when appropriate. In addition, quality of life should be a priority in the care of elderly patients and patient-reported outcomes should be assessed and reported.

European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium.

The purpose of this guideline is to present evidence-based and consensus-based recommendations for the prevention and treatment of postoperative delirium. The cornerstones of the guideline are the preoperative identification and handling of patients at risk, adequate intraoperative care, postoperative detection of delirium and management of delirious patients. The scope of this guideline is not to cover ICU delirium. Considering that many medical disciplines are involved in the treatment of surgical patients, a team-based approach should be implemented into daily practice. This guideline is aimed to promote knowledge and education in the preoperative, intraoperative and postoperative setting not only among anaesthesiologists but also among all other healthcare professionals involved in the care of surgical patients.

Global cancer surgery: delivering safe, affordable, and timely cancer surgery.

Surgery is essential for global cancer care in all resource settings. Of the 15.2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US $6.2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery--e.g., pathology and imaging--are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning.

EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma.

PURPOSE: Sentinel lymph node biopsy is an essential staging tool in patients with clinically localized melanoma. The harvesting of a sentinel lymph node entails a sequence of procedures with participation of specialists in nuclear medicine, radiology, surgery and pathology. The aim of this document is to provide guidelines for nuclear medicine physicians performing lymphoscintigraphy for sentinel lymph node detection in patients with melanoma. METHODS: These practice guidelines were written and have been approved by the European Association of Nuclear Medicine (EANM) to promote high-quality lymphoscintigraphy. The final result has been discussed by distinguished experts from the EANM Oncology Committee, national nuclear medicine societies, the European Society of Surgical Oncology (ESSO) and the European Association for Research and Treatment of Cancer (EORTC) melanoma group. The document has been endorsed by the Society of Nuclear Medicine and Molecular Imaging (SNMMI). CONCLUSION: The present practice guidelines will help nuclear medicine practitioners play their essential role in providing high-quality lymphatic mapping for the care of melanoma patients.

The balance of clinician and patient input into treatment decision-making in older women with operable breast cancer.

OBJECTIVE: Primary endocrine therapy (PET) is an alternative to surgery for oestrogen receptor positive operable breast cancer in some older women. However the decision to offer PET involves complex trade-offs and is influenced by both patient choice and healthcare professional (HCP) preference. This study aimed to compare the views of patients and HCPs about this decision and explore decision-making (DM) preferences and whether these are taken into account during consultations. METHODS: This multicentre, UK, mixed methods study had three components: (a) questionnaires to older women undergoing counseling about breast cancer treatment options which assessed their DM preferences and realities; (b) qualitative interviews with older women with operable breast cancer offered a choice of either surgery or PET and (c) qualitative interviews with HCPs (both of which focused on DM preferences in this setting). RESULTS: Thirty-three patients and 34 HCPs were interviewed. A range of opinions about patient involvement in DM were identified. Patients indicated varying preferences for DM involvement which were variably taken into account by HCPs. These qualitative findings were broadly supported by the questionnaire results. Most patients (536/729; 73.5%) achieved their preferred DM style; however, the remainder felt that their DM preferences had not been taken into consideration. CONCLUSIONS: These results suggest that whilst many older women achieve their desired level of DM engagement, some do not, raising the possibility that they may be making choices which are not concordant with their treatment preferences.

Localization techniques for guided surgical excision of non-palpable breast lesions.

BACKGROUND: Breast cancer is the most common form of cancer and the second leading cause of death amongst women in Europe. Amongst five invasive cancers per 1000 women detected in screening, 2.7 were < 15 mm in diameter; and others reported that over one third of excised breast lesions were clinically occult. The challenge is to accurately locate small non-palpable lesions intraoperatively for optimal therapeutic outcome. A secondary important goal is to remove the smallest amount possible of healthy glandular tissue for optimal cosmesis. Currently the most widely adopted approach (80% in one survey) in guided breast-conserving surgery for excising non-palpable breast lesions is wire-guided localization (WGL). With the clinical setting shifting towards earlier non-palpable breast lesions being detected through screening, we investigated whether the current standard in assisting surgical excision of these lesions, WGL, yields the best therapeutic outcome for women with breast cancer. OBJECTIVES: To assess the therapeutic outcomes of any new form of guided surgical intervention for non-palpable breast lesions against wire-guided localization, the current gold standard. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCG) Specialized Register, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal from the earliest available date up to 30 March 2015. We also handsearched recent conference proceedings and sought information from experts in the field. SELECTION CRITERIA: Two review authors, BC and RJ, independently screened by title and abstract the studies we had identified through the search strategy; when this was inconclusive, they examined the full-text article for inclusion. We resolved any discrepancies regarding eligibility by discussion with a third review author, RA. DATA COLLECTION AND ANALYSIS: Three review authors, BC, JW, and RJ, independently extracted data using a standardized data sheet. We performed all analyses using Review Manager (RevMan) or the R meta package, and in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We reported results via a graphical assessment using forest plots showing the study estimates. We considered and discussed additional subgroup and sensitivity analyses. MAIN RESULTS: We identified 11 randomized controlled trials (RCTs) that met the inclusion criteria of this Cochrane review and included eight trials in the meta-analyses. Six RCTs compared radioguided occult lesion localization (ROLL) versus WGL, and two RCTs compared radioactive iodine ((125)I) seed localization (RSL) versus WGL. Of the three remaining trials, one RCT compared cryo-assisted techniques (CAL) versus WGL, one compared intraoperative ultrasound-guided lumpectomy (IOUS) versus WGL, and one compared modified ROLL technique in combination with methylene dye (RCML) versus WGL. Of the trials we included in the meta-analysis, there were a total of 1273 participants with non-palpable breast lesions (627 participants (WGL); 443 participants (ROLL); and 203 participants (RSL)). The participant population varied considerably between included trials, which included participants with both non-palpable benign and malignant lesions, and varied in defining clear margins. The included trials did not report any long-term outcomes.In general, the outcomes of WGL, ROLL and RSL were comparable.ROLL demonstrated favourable results in successful localization (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.16 to 2.28; 869 participants; six trials), positive excision margins (RR 0.74, 95% CI 0.42 to 1.29; 517 participants; five trials), and re-operation rates (RR 0.51, 95% CI 0.21 to 1.23; 583 participants; four trials) versus WGL, but none were statistically significant. WGL was significantly superior to RSL in successfully localizing non-palpable lesions (RR 3.85, 95% CI 1.21 to 12.19; 402 participants; two trials). However, for successful excision, ROLL and RSL have comparable outcomes versus WGL (ROLL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 871 participants; six trials; RSL versus WGL: RR 1.00, 95% CI 0.99 to 1.01; 402 participants; two trials). These findings were similar in that RSL demonstrated favourable results over WGL in positive tumour margins (RR 0.67, 95% CI 0.43 to 1.06; 366 participants; two trials), and re-operation rates (RR 0.80, 95% CI 0.48 to 1.32; 305 participants; one trial) but neither reached statistical significance. In contrast, WGL had fewer postoperative complications to both ROLL (RR 1.18, 95% CI 0.71 to 1.98; 642 participants; four trials) and RSL (RR 1.51, 95% CI 0.75 to 3.03; 305 participants; one trial), although this was also not statistically significant.The overall quality of evidence was good. The main risk of bias amongst included studies consisted of incomplete data sets, selective reporting, and allocation concealment. Interpretation and applicability of this meta-analysis was hindered by the mixed indication of diagnostic versus therapeutic purposes when undertaking WGL, ROLL, or RSL, leading to a high level of mixed pathology in numerous trials. Other limitations include underpowered studies, lack of data in standardized format for meta-analysis, lack of complete data amongst the trials, and absence of long-term data. AUTHORS' CONCLUSIONS: Owing to a lack of trials in certain localization techniques, we could only draw conclusions about ROLL and RSL versus WGL. There is no clear evidence to support one guided technique for surgically excising a non-palpable breast lesion over another. Results from this Cochrane review support the continued use of WGL as a safe and tested technique that allows for flexibility in selected cases when faced with extensive microcalcification. ROLL and RSL could be offered to patients as a comparable replacement for WGL as they are equally reliable. Other techniques such as IOUS, RCML, and CAL are of academic interest, but recommendation for routine use in the clinical environment and oncological outcomes require further validation. The results of this Cochrane review also stress the need for more fully powered RCTs to evaluate the best technique according to the comprehensive criteria described, with a more consistent and standardized approach in outcome reporting.