乳腺癌内乳淋巴结放疗是否利大于弊？
乳腺癌可转移至区域淋巴结，首先是腋窝和乳房内侧（内乳）淋巴结，随后是锁骨上内侧淋巴结。腋窝淋巴结阴性患者的内乳淋巴结转移率仅4%～9%，而腋窝淋巴结阳性患者的内乳淋巴结转移率达16%～65%。因此，对于腋窝淋巴结阳性患者，乳腺癌局部治疗除了手术切除原发肿瘤和腋窝淋巴结，还包括有选择地对未切除的内乳和锁骨上内侧淋巴结进行区域淋巴结放疗。若干单项研究10年随访结果和荟萃分析表明，乳房切除术后对部分或全部区域淋巴结进行放疗，可改善无病生存和无远处转移生存，减少乳腺癌所致死亡风险。不过，既往研究还发现，由于放疗可能影响心脏，故非乳腺癌所致死亡风险也有所增加，从而影响总生存。该不确定性导致某些医院对复发风险较高患者继续进行区域淋巴结放疗，而其他医院对区域淋巴结放疗限制较多，尤其对于心脏附近的内乳淋巴结。因此，有必要开展大样本随机对照临床研究，对内乳淋巴结放疗的生存结局进行长期随访。
2020年11月2日，英国《柳叶刀》肿瘤学分册在线发表比利时安特卫普大学肿瘤放疗中心、荷语天主教鲁汶大学医院、法语天主教鲁汶大学圣卢克医院、法国乔治斯-弗朗索瓦·勒克莱尔癌症中心、古斯塔夫·鲁西癌症中心、居里研究院、斯特拉斯堡欧洲癌症研究中心、莱昂·贝拉德癌症中心、德国柏林大学夏里特医学院综合癌症中心、图宾根大学、荷兰乌德勒支大学、代芬特尔放疗中心、阿姆斯特丹大学、特文特综合医院、佛比滕研究所蒂尔堡医院、莱顿大学、荷兰癌症研究所、意大利圣安娜医院、瑞士苏黎世大学、以色列兰巴姆医院的欧洲癌症研究与治疗组织（EORTC）22922/10925研究报告，对I～III期乳腺癌患者术后±内乳和锁骨上内侧淋巴结放疗的15年生存结局进行了比较。
NCT00002851 (EORTC 22922/10925): Lymph Node Radiation Therapy in Patients With Stage I, Stage II, or Stage III Breast Cancer That Has Been Surgically Removed (Phase III Randomised Trial Investigating The Role of Internal Mammary and Medial Supraclavicular Lymph Node Chain Irradiation in Stage I-III Breast Cancer)
该国际多中心随机对照三期临床研究于1996年8月5日～2004年1月13日从13个国家或地区46个肿瘤放疗科入组年龄≤75岁、经组织学证实为I～III期单侧乳腺癌且腋窝淋巴结肿大或原发肿瘤位于乳房内侧的4004例女性。手术包括乳房切除术或保乳手术和腋窝分期。通过集中最小化随机法将患者按1∶1分为两组：
放疗组2002例：进行内乳和锁骨上内侧淋巴结放疗（50戈瑞分割为25次）
对照组2002例：不行内乳和锁骨上内侧淋巴结放疗
对医院、绝经状态、乳房内原发肿瘤部位、乳房和腋窝手术类型、病理T和N分期进行分层。患者和研究者对治疗分配非盲。主要终点为根据意向治疗原则分析的总生存。次要终点包括无病生存、无远处转移生存、乳腺癌死亡、乳腺癌复发、死亡原因。随机分组后，进行20年随访。
结果，中位随访15.7年（四分位14.0～17.6）期间，放疗组与对照组相比：
死亡数量：554例比569例（27.7%比28.4%）
死亡原因：相似
总体生存比例：73.1%比70.9%（95%置信区间：71.0～75.2、68.6～72.9）
总体死亡风险：相似（风险比：0.95，95%置信区间：0.84～1.06，P=0.36）
乳腺癌复发比例：24.5%比27.1%（95%置信区间：22.5～26.6、25.1～29.2）
乳腺癌复发风险：低13%（风险比：0.87，95%置信区间：0.77～0.98，P=0.024）
乳腺癌死亡比例：16.0%比19.8%（95%置信区间：14.3～17.7、18.0～21.7）
乳腺癌死亡风险：低19%（风险比：0.81，95%置信区间：0.70～0.94，P=0.0055）
无病生存比例：60.8%比59.9%（95%置信区间：58.4～63.2、57.5～62.2）
发病死亡风险：相似（风险比：0.93，95%置信区间：0.84～1.03，P=0.18）
无远处转移生存比例：70.0%比68.2%（95%置信区间：67.7～72.2、65.9～70.3）
远处转移或死亡比例：相似（风险比：0.93，95%置信区间：0.83～1.04，P=0.18）
因此，该研究15年结果表明，对于I～III期乳腺癌，内乳和锁骨上内侧淋巴结放疗与未放疗相比，乳腺癌死亡、乳腺癌复发都显著较少，总生存、无病生存、无远处转移生存相似。
对此，英国剑桥大学、伦敦大学癌症研究院、皇家马斯登医院发表同期评论：乳腺癌内乳淋巴结放疗是否利大于弊？
读者投票
Lancet Oncol. 2020 Nov 2. Online ahead of print.
Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
Poortmans PM, Weltens C, Fortpied C, Kirkove C, Peignaux-Casasnovas K, Budach V, van der Leij F, Vonk E, Weidner N, Rivera S, van Tienhoven G, Fourquet A, Noel G, Valli M, Guckenberger M, Koiter E, Racadot S, Abdah-Bortnyak R, Van Limbergen EF, Engelen A, De Brouwer P, Struikmans H, Bartelink H; European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups.
Iridium Kankernetwerk, Wilrijk-Antwerp, Belgium; University of Antwerp, Wilrijk-Antwerp, Belgium; University Hospital Leuven, Leuven, Belgium; KU Leuven, Leuven, Belgium; European Organisation for Research and Treatment of Cancer, Brussels, Belgium; University Hospital Saint Luc, Université Catholique de Louvain, Brussels, Belgium; Centre Georges Francois Leclerc, Dijon, France; Gustave Roussy Cancer Centre, Villejuif, France; Institut Curie, Paris, France; Institut de Cancérologie Strasbourg-Europe, Strasbourg, France; Centre Léon Bérard, Lyon, France; Comprehensive Cancer Center, Charite University Medicine, Berlin, Germany; University Hospital, Tübingen, Germany; University Medical Centre Utrecht, Utrecht, Netherlands; Radiotherapiegroep, Deventer, Netherlands; Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Netherlands; Medisch Spectrum Twente, Enschede, Netherlands; Institute Verbeeten, Tilburg, Netherlands; Leiden University Medical Centre, Leiden, Netherlands; Netherlands Cancer Institute, Amsterdam, Netherlands; Sant Anna Hospital, Como, Italy; University Hospital Zurich, University of Zurich, Switzerland; Rambam Health Care Campus, Haifa, Israel.
BACKGROUND: 10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation.
METHODS: EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I-III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851.
FINDINGS: Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15.7 years (IQR 14.0-17.6), 554 (27.7%) patients in the IM-MS irradiation group and 569 (28.4%) patients in the control group had died. Overall survival was 73.1% (95% CI 71.0-75.2) in the IM-MS irradiation group and 70.9% (68.6-72.9) in the control group (HR 0.95 [95% CI 0.84-1.06], p=0.36). Any breast cancer recurrence (24.5% [95% CI 22.5-26.6] vs 27.1% [25.1-29.2]; HR 0.87 [95% CI 0.77-0.98], p=0.024) and breast cancer mortality (16.0% [14.3-17.7] vs 19.8% [18.0-21.7]; 0.81 [0.70-0.94], p=0.0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60.8% [95% CI 58.4-63.2] vs 59.9% [57.5-62.2]; HR 0.93 [95% CI 0.84-1.03], p=0.18), or distant metastasis-free survival (70.0% [67.7-72.2] vs 68.2% [65.9-70.3]; 0.93 [0.83-1.04], p=0.18). Causes of death between groups were similar.
INTERPRETATION: The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I-III breast cancer. However, this is not converted to improved overall survival.
FUNDING: US National Cancer Institute, Ligue Nationale contre le Cancer, KWF Kankerbestrijding
PMID: 33152277
DOI: 10.1016/S1470-2045(20)30472-1
Lancet Oncol. 2020 Nov 2. Online ahead of print.
Internal mammary node irradiation in breast cancer: does benefit outweigh risk?
Coles CE, Haviland JS, Kirby AM.
University of Cambridge, Cambridge, UK; Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.
PMID: 33152276
DOI: 10.1016/S1470-2045(20)30551-9