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8年前，美国临床肿瘤学会、外科肿瘤学会、美国放射肿瘤学会联合发表指南，根据对33项研究2万8162例早期乳腺浸润癌患者保乳手术切缘与局部复发数据的荟萃分析，推荐将保乳手术切缘墨染处无肿瘤作为安全切缘标准，足以减少局部复发。不过，根据目前对大多数乳腺癌患者进行术后全身治疗的做法，最常见的首次复发部位为远处复发，而非局部复发。可见，大多数远处复发并非由于已经局部复发。 2022年9月21日，国际四大医学期刊之一、英国医学会《英国医学杂志》正刊发表英国利兹大学圣詹姆斯医院、曼彻斯特大学医院、南安普顿大学医院、独立癌症患者之声、牛津大学、南澳大利亚大学、澳大利亚国立大学医学院坎培拉医院、德国癌症研究中心、萨尔兰州癌症登记中心的研究报告，通过事先注册的文献系统回顾和荟萃分析，确定切缘受累是否与远处复发相关，并确定最大限度减少早期乳腺浸润癌局部复发和远处复发所需的切缘。 该研究对Medline（PubMed）、Embase和Proquest在线数据库1980年1月1日～2021年12月31日已发表研究以及该研究作者未发表数据进行系统回顾和荟萃分析。符合条件的研究报告了I～III期乳腺癌保乳术后病理检查切缘状态以及随访至少60个月的患者相关结局。仅有导管原位癌或接受新辅助化疗或乳房切除术治疗的患者被剔除。切缘被分类为切缘受累（墨染处有肿瘤）、切缘接近（虽然墨染处无肿瘤，但是切缘<2毫米）和切缘阴性（切缘≥2毫米）。 结果，68项研究符合条件，其中11万2140例乳腺癌患者被纳入荟萃分析。 
BMJ 2022 Sep 21;378:e070346. Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis. Bundred JR, Michael S, Stuart B, Cutress RI, Beckmann K, Holleczek B, Dahlstrom JE, Gath J, Dodwell D, Bundred NJ. University of Leeds, Leeds, UK; St James University Hospital, Leeds, UK; Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK; University of Manchester, Manchester, UK; University of Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK; Independent Cancer Patients' Voice, London, UK; University of Oxford, Oxford, UK; University of South Australia, Adelaide, SA, Australia; Canberra Health Services and Australian National University Medical School, ACT, Australia; German Cancer Research Centre (DKFZ), Heidelberg, Germany; Saarland Cancer Registry, Saarbrücken, Germany. OBJECTIVE: To determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer. DESIGN: Prospectively registered systematic review and meta-analysis of literature. DATA SOURCES: Medline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors. ELIGIBILITY CRITERIA: Eligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but <2 mm), and negative margins (≥2 mm). RESULTS: 68 studies from 1 January 1980 to 31 December 2021, comprising 112140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, P<0.001) and local recurrence (1.98, 1.66 to 2.36, P<0.001). Close margins were associated with increased distant recurrence (1.38, 1.13 to 1.69, P<0.001) and local recurrence (2.09, 1.39 to 3.13, P<0.001) compared with negative margins, after adjusting for receipt of adjuvant chemotherapy and radiotherapy. In five studies published since 2010, tumour on ink margins were associated with increased distant recurrence (2.41, 1.81 to 3.21, P<0.001) as were tumour on ink and close margins (1.44, 1.22 to 1.71, P<0.001) compared with negative margins. CONCLUSIONS: Involved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised. SYSTEMATIC REVIEW REGISTRATION: CRD42021232115 PMID: 36130770 DOI: 10.1136/bmj-2022-070346 BMJ 2022 Sep 21;378:o2077. Width of excision margins after breast conserving surgery for invasive breast cancer and distant recurrence and survival. Bundred NJ, Bundred JR, Cutress RI, Dodwell D. Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK; University of Manchester, Manchester, UK; University of Leeds, Leeds, UK; St James University Hospital, Leeds, UK; University of Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK; University of Oxford, Oxford, UK. One premise of cancer treatment is that if a tumour is cut out but tumour cells remain present or close to the edges (of the cut), the risk of cancer returning at the same site is increased. Increased surgical focus on adequacy of margin excision would improve breast cancer survival worldwide. IMPORTANCE OF TUMOUR REMOVAL In many cancers, such as colorectal cancer, attention to ensuring meticulous removal of the cancer with an encompassing cuff of normal tissue (ie, no tumour at the pathological margin) results in improved outcomes. The association between margin involvement and poorer recurrence and survival outcomes led to studies that showed a strong association between the width of tumour from the margin in colorectal cancer and subsequent outcomes. Most patients with early breast cancer are treated with breast conserving surgery. Removing cancers without leaving malignant cells at a surgical margin reduces local recurrence but the effects of margin involvement on distant recurrence and mortality are unclear. How far the tumour should be from the specimen margin to ensure optimum oncological outcomes is contentious. THE DEFINITION OF A CLEAR MARGIN MATTERS When cancer is surgically removed, the tumour is subject to pathological examination. The edges of the removed cancer specimens, known as the margins, can be either microscopically involved, in that the tumour is at the edge of the specimen, or not involved, that is, no tumour is seen at the edge. The distance from the edge of the margin to the tumour is measured. A close margin occurs when the tumour is not at the edge but within a given distance; usually 1 mm or 2 mm. Close margins are important because pathological assessment provides a representative sample of material examined. Involved or close margins are associated with between 39% and 85% patients having residual cancer after re-excision surgery. Occult foci of disease occur beyond the apparent edge of cancers and might not be adequately treated by adjuvant treatment. Internationally, proportions of surgical margins involvement for breast cancer vary from 9.4% to 17.8% depending on definition of involvement. A meta-analysis of 14571 patients reported findings that a 1 mm margin of normal tissue around invasive cancer after breast conserving surgery was reasonable.3 In 2009, UK British Association of Surgical Oncology guidelines5 did not recommend a specific width of clearance around invasive cancers, and 21% of patients had tumours with less than 1 mm from margins in a large UK study.9 In 2014, an authoritative US guideline advised that avoiding the presence of cancer touching the margin (known as tumour on ink) was sufficient to minimise local recurrence. The National Institute for Health and Care Excellence (known as NICE) did not define a minimum margin distance but suggested that the benefits of further surgery should be discussed with the patient where margins were close but not on the edge. Differences in guidelines have led to confusion about the correct approach to surgical margins. Local recurrence is associated with higher rates of death from breast cancer. Globally, local recurrence rates after breast surgery have reduced from 20% before widespread adjuvant treatment use to 5% or lower currently. The effect of both adjuvant systemic treatment and radiotherapy in reducing local and distant recurrence has probably influenced the interpretation of the significance of margin proximity. To answer the questions of whether involved or close margins are associated with increased distant recurrence and decreased overall survival, we conducted a prospectively registered systematic review of all the available literature according to PRISMA guidelines. Patient pathology specimens were categorised as tumour at the margin (involved), close margins (tumour <2 mm from the margin, but not at the margin), and negative margins (tumour ≥2 mm from the margin). We included 68 studies comprising 112140 patients undergoing breast conserving surgery. Overall, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had tumour at the margin and 17.8% (13.0% to 23.9%) had tumours at or close to the margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour at the margin, 8.4% (4.4% to 15.5%) with tumours at or close to margins, and 7.4% (3.9% to 13.6%) patients with negative margins. On multivariable analyses, importantly taking into account postoperative chemotherapy and radiotherapy, involved margins compared with negative margins were associated with increased distant recurrence (hazard ratio 2.10 (95% confidence interval 1.65 to 2.69), P<0.001) and local recurrence (1.98 (1.66 to 2.36)). Compared with negative margins, close margins were associated with increased distant recurrence (1.38 (1.13 to 1.69), P<0.001) and local recurrence (2.09 (1.39 to 3.13), P<0.001), after adjusting for receipt of adjuvant chemotherapy and radiotherapy. LIMITATIONS This review collates data from more than five times the number of patients in the 2014 US consensus guideline addressing local recurrence and surgical margins.6 As with previous analyses, most of these data are from cohort studies, not randomised trials, thus a causal association between margin proximity and distant recurrence cannot be proven. Given the unavoidable absence of randomised evidence on the consequences of margin proximity, these findings plausibly indicate that clearance of margins in invasive breast cancer should remain a priority to reduce both distant and local recurrence irrespective of the increased use of adjuvant treatments. WHY SURGICAL TUMOUR MARGINS MATTER Current international guidelines need revision to account for these findings. Recognising that wider margins might require further surgery, decisions about re-excision should be the product of an informed discussion between clinicians and patients. The issue of involved margins after breast conservation might not be routinely discussed with patients but patient advocates believed that complete surgical excision to prevent distant recurrence was more important to them than cosmesis. In multidisciplinary team meetings, opinions vary about what margin width is acceptable for invasive and in situ cancer. International guidelines on the optimal width for margin clearance should be based on the width to prevent distant recurrence as a primary aim. Wider margins should not necessarily increase mastectomy rates but might require more specific preoperative multidisciplinary team planning of surgical incisions and operations. CONCLUSIONS These comprehensive data indicate the likelihood that inadequate margin width results in higher risks of distant recurrence and breast cancer mortality, as well as increased local recurrence. Involving patients with cancer in discussions about margin clearance before surgery should be an essential part of informed consent for surgery. Increased surgical focus on adequacy of margin excision would improve breast cancer survival worldwide. PMID: 36130769 DOI: 10.1136/bmj.o2077
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