丧钟为乳腺癌腋窝淋巴结清扫而鸣

　　对于早期乳腺癌，如果腋窝淋巴结临床检查阴性、但是前哨淋巴结活检1或2枚阳性，美国外科医师学会肿瘤学组（ACOSOG）于2011年公布的Z0011研究和欧洲癌症研究与治疗组织（EORTC）于2014年公布的AMAROS研究已经证实，保乳手术或乳房切除术后可免腋窝淋巴结清扫，以减少上肢淋巴水肿，但是由于研究设计非劣效性边界过宽、样本量较小导致统计学效力不足、淋巴结放疗靶区及术后全身治疗不确定、乳房切除术患者未入组或入组较少（17.4%）、前哨淋巴结转移灶微转移比例较高（约40%）、研究过早结束等原因，这两项研究结果备受质疑。为此，瑞典卡罗林斯卡学院、瑞典研究委员会、瑞典癌症基金会、北欧癌症联盟于2015年联合发起SENOMAC研究。

SENOMAC (NCT02240472): Sentinel Node Biopsy in Breast Cancer: Omission of Axillary Clearance After Macrometastases. A Randomized Trial (Survival and Axillary Recurrence Following Sentinel Node-positive Breast Cancer Without Completion Axillary Lymph Node Dissection - a Randomized Study of Patients With Macrometastases in the Sentinel Node)

　　2024年4月4日正值清明节，国际四大医学期刊之一的美国麻省医学会《新英格兰医学杂志》在线发表瑞典卡罗林斯卡学院、卡皮奥圣戈兰医院、斯德哥尔摩南方医院、隆德大学、哥德堡大学、于默奥大学、厄勒布鲁大学、瑞典中部地区癌症中心、斯卡拉堡医院、林雪平大学、乌普萨拉大学西曼兰医院、丹麦哥本哈根大学根措夫特医院、维堡医院、奥尔堡大学、瓦埃勒医院、南丹麦大学、奥胡斯大学、丹麦粒子治疗中心、德国罗斯托克大学、菲尔德医院、乌尔姆大学、希腊雅典大学、意大利圣拉斐尔生命健康大学、芬兰赫尔辛基大学的SENOMAC研究次要终点分析报告。

　　该国际多中心非劣效研究于2015年1月31日至2021年12月31日从瑞典、丹麦、德国、希腊、意大利5个国家67家医院入组临床淋巴结阴性、T1至T3期（肿瘤最大直径：T1期≤20毫米、T2期21～50毫米、T3期>50毫米）并且1或2枚前哨淋巴结宏转移（转移灶最大直径>2毫米）的原发乳腺癌患者2540例，按1∶1的比例随机分成两组：单纯活检组1335例前哨淋巴结活检后免腋窝淋巴结清扫、活检清扫组1205例前哨淋巴结活检后予腋窝淋巴结清扫。主要终点为总生存，次要终点为无复发生存。预设复发或死亡风险比的95%置信区间上限必须低于1.44，才能证明单纯活检组与活检清扫组相比非劣效。

　　结果，单纯活检组1326例和活检清扫组1197例患者随访至少12个月，其中1192例（89.9%）和1058例（88.4%）完成淋巴结靶区放疗。

　　中位随访46.8个月（范围1.5～94.5），共计191例患者复发或死亡。

　　单纯活检组与活检清扫组相比：

• 估计5年无复发生存率：89.7%比88.7%（95%置信区间：87.5～91.9、86.3～91.1）
• 对国别校正后复发或死亡风险比：0.89（95%置信区间：0.66～1.19，显著低于预设非劣效界值1.44，P<0.001）

　　亚组分析表明：无论患者年龄是否小于65岁、肿瘤是否大于50毫米、1或2枚、是否小叶癌、保乳或乳房切除、是否侵犯包膜外、雌激素受体和HER2阳性或阴性、年份，单纯活检与活检清扫相比，复发或死亡风险都相似（除了雌激素受体和HER2同时阳性乳腺癌，单纯活检与活检清扫相比，复发或死亡风险显著较低）。

　　因此，该研究结果进一步证实：对于临床淋巴结阴性、1或2枚前哨淋巴结宏转移的T1至T3期乳腺癌保乳或乳房切除患者，其中大多数进行淋巴结放疗，单纯活检与活检清扫相比，5年无复发生存率相似。

　　对此，美国弗吉尼亚联邦大学发表同期评论：丧钟为腋窝清扫而鸣。

N Engl J Med. 2024 Apr 4;390(13):1163-1175. IF: 158.5

Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

Jana de Boniface, Tove Filtenborg Tvedskov, Lisa Rydén, Robert Szulkin, Toralf Reimer, Thorsten Kühn, Michalis Kontos, Oreste D. Gentilini, Roger Olofsson Bagge, Malin Sund, Dan Lundstedt, Matilda Appelgren, Johan Ahlgren, Sophie Norenstedt, Fuat Celebioglu, Helena Sackey, Inge Scheel Andersen, Ute Hoyer, Per F. Nyman, Eva Vikhe Patil, Elinore Wieslander, Henrik Dahl Nissen, Sara Alkner, Yvette Andersson, Birgitte V. Offersen, Leif Bergkvist, Jan Frisell, Peer Christiansen; SENOMAC Trialists' Group.

Karolinska Institutet, Capio St. Goran's Hospital, Cytel; Sodersjukhuset, Breast Center Karolinska, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm; Lund University, Skane University Hospital Lund, Lund; Skane University Hospital Lund, Malmo; Sahlgrenska Academy at Gothenburg University, Sahlgrenska University Hospital, Gothenburg; Umea University, Umea; Orebro University, Orebro; Regional Cancer Center of Mid-Sweden, Uppsala; Skaraborg Hospital, Lidkpoing; Linkpoing University, Linkoping University Hospital, Linkoping; Uppsala University and Region Vastmanland, Vastmanland Hospital, Vasteras, Sweden. University of Copenhagen, Gentofte Hospital, Gentofte; Viborg Hospital, Viborg; Aalborg University Hospital, Aalborg; Vejle Hospital, University Hospital of Southern Denmark, Vejle; Aarhus University Hospital, Aarhus University, Danish Center for Particle Therapy, Aarhus, Denmark; University of Rostock, Rostock; Die Filderklinik, Filderstadt; University of Ulm, Ulm, Germany; National and Kapodistrian University of Athens, Athens; IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan; University of Helsinki and Helsinki University Hospital, Helsinki.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups.

METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44.

RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin.

CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy.

Funded by the Swedish Research Council and others

SENOMAC ClinicalTrials.gov number: NCT02240472

DOI: 10.1056/NEJMoa2313487

N Engl J Med. 2024 Apr 4;390(13):1231-1232. IF: 158.5

Axillary Dissection - The Bell Tolls for Thee.

Kandace P. McGuire.

Virginia Commonwealth University, Richmond.

DOI: 10.1056/NEJMe2401805

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