{"product_id":"skipping-full-armpit-lymph-node-removal-is-safe-for-patients-with-node-negative-breast-cancer-and-one-or-two-sentinel-node-macrometastases-who-receive-guideline-directed-treatment","title":"Skipping Full Armpit Lymph Node Removal Is Safe for Patients with Node-Negative Breast Cancer and One or Two Sentinel-Node Macrometastases Who Receive Guideline-Directed Treatment","description":"\u003cp\u003eIn a large international trial, 2,766 patients had early breast cancer with cancer cells found in one or two sentinel lymph nodes. Skipping the more extensive removal of additional armpit lymph nodes (completion axillary-lymph-node dissection) did not worsen outcomes compared with having that surgery. The estimated 5-year recurrence-free survival was 89.7% in the group that had only the sentinel-node biopsy and 88.7% in the group that had the full dissection. The result met the trial's strict definition of noninferiority (P\u0026lt;0.001), meaning the simpler surgery was statistically shown not to be worse. Most patients in both groups also received radiation therapy that included the lymph-node regions.\u003c\/p\u003e\n\n\u003ch1\u003eSkipping Full Armpit Lymph Node Removal Is Safe for Patients with Node-Negative Breast Cancer and One or Two Sentinel-Node Macrometastases Who Receive Guideline-Directed Treatment\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Question Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#patients\"\u003eWho Took Part in the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#findings\"\u003eKey Findings: Recurrence-Free Survival\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#subgroups\"\u003eResults in Specific Patient Groups\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a trial of 2,766 patients with early breast cancer and one or two sentinel-node macrometastases, skipping completion axillary-lymph-node dissection did not worsen 5-year recurrence-free survival.\u003c\/li\u003e\n\u003cli\u003eEstimated 5-year recurrence-free survival was 89.7% with sentinel-node biopsy only and 88.7% with full dissection, meeting the trial's strict noninferiority definition.\u003c\/li\u003e\n\u003cli\u003eMost patients in both groups received radiation therapy that included the lymph-node regions, and all but 26 received some systemic treatment.\u003c\/li\u003e\n\u003cli\u003eCompletion dissection carries a higher risk of long-term complications, especially lymphedema; in an earlier trial, lymphedema signs were twice as common after dissection as after axillary radiation.\u003c\/li\u003e\n\u003cli\u003eThe clinical trial's median follow-up was 46.8 months; the primary analysis of overall survival has not yet reached full statistical power, though estimated 5-year overall survival was 92.9% with sentinel-node biopsy only and 92.0% with full dissection, and subgroup findings should be interpreted with caution.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Question Matters\u003c\/h2\u003e\n\n\u003cp\u003eWhen breast cancer spreads, it often travels first to the lymph nodes in the armpit (the axilla). Surgeons have long removed these lymph nodes to check for cancer and to help control the disease. The first nodes to receive cancer cells are called \u003cstrong\u003esentinel lymph nodes\u003c\/strong\u003e. A procedure called \u003cstrong\u003esentinel-node biopsy\u003c\/strong\u003e removes only these first nodes for testing.\u003c\/p\u003e\n\n\u003cp\u003eIf cancer is found in a sentinel node, doctors have traditionally performed a second, larger operation. This operation is called \u003cstrong\u003ecompletion axillary-lymph-node dissection\u003c\/strong\u003e. It removes many more lymph nodes from the armpit. This more extensive surgery can cause long-term problems, especially \u003cstrong\u003elymphedema\u003c\/strong\u003e (painful swelling of the arm caused by fluid buildup).\u003c\/p\u003e\n\n\u003cp\u003eIn 2010 and 2011, the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial showed that skipping the completion dissection was safe for certain patients. Those patients had breast-conserving surgery (removing only the tumor and some surrounding tissue) plus whole-breast radiation therapy. They also had one or two sentinel-node metastases (cancer spread to the sentinel nodes).\u003c\/p\u003e\n\n\u003cp\u003eSince then, the use of completion axillary-lymph-node dissection has steadily decreased. However, in some countries, guidelines changed slowly. The reasons included problems with the earlier trials. The ACOSOG Z0011 trial had too few patients enrolled and closed early. The trial used a large noninferiority margin (a wide allowance for how much worse a treatment could be) and had short follow-up. There were also uncertainties about which lymph-node regions received radiation and what this meant for additional treatments.\u003c\/p\u003e\n\n\u003cp\u003eIn a later report, the ACOSOG Z0011 investigators found that more than half of the patients had received postoperative radiation therapy. That radiation therapy used high tangents (a radiation technique that reaches into the armpit). In addition, 19% received nodal radiation therapy that the protocol did not allow. Detailed treatment records were available for only 228 of 856 patients.\u003c\/p\u003e\n\n\u003cp\u003eAnother trial, the European Organization for Research and Treatment of Cancer (EORTC) 10981-22023 AMAROS trial, replaced completion dissection with axillary radiation therapy. Mastectomy (complete removal of the breast) was not a reason to exclude patients, but only 248 patients (17.4%) who had a mastectomy underwent randomization. Neither trial reached enough statistical power for its goals. Still, after 10 years of follow-up, no benefit of completion axillary-lymph-node dissection was observed. However, signs of lymphedema were twice as common after completion dissection as after axillary radiation therapy in the AMAROS trial.\u003c\/p\u003e\n\n\u003cp\u003eIn 2015, the researchers opened the SENOMAC trial. The goal was to confirm the earlier results in a large enough group. The trial focused only on patients with sentinel-node macrometastases (cancer deposits larger than 2 mm). It also included important groups that had been underrepresented before. These groups included patients having a mastectomy, patients with extracapsular extension (cancer growing outside the lymph node capsule), patients with T3 tumors (larger than 50 mm), and men.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eSENOMAC was a prospective, randomized, phase 3 trial. \"Prospective\" means patients were followed forward in time. \"Randomized\" means patients were assigned to treatment groups by chance. \"Phase 3\" means it was a large trial designed to confirm effectiveness.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers chose a noninferiority design. This type of design tests whether a simpler treatment is not worse than the standard treatment by more than a small, acceptable amount. The researchers chose this design because sentinel-node biopsy is known to have advantages for long-term complications, such as lymphedema.\u003c\/p\u003e\n\n\u003cp\u003eThe trial aimed to show that omitting completion axillary-lymph-node dissection would not worsen overall survival by more than a small, clinically acceptable margin. The original trial protocol has been published previously. The authors confirm that the data are complete and accurate and that the trial followed the protocol.\u003c\/p\u003e\n\n\u003cp\u003eThe trial took place at 67 hospitals in five countries: Sweden, Denmark, Germany, Greece, and Italy. Ethics approval came from the Swedish Ethical Review Authority in 2014 and from relevant review boards in the participating countries. All patients gave informed written consent. The trial followed Good Clinical Practice guidelines. Clinical data were recorded in an electronic case-report form, and data quality was carefully reviewed to address any unusual, missing, or inconsistent values.\u003c\/p\u003e\n\n\u003cp\u003eThe manuscript was written by the authors. No one who was not an author contributed to writing the manuscript. The funders had no role in the design, performance, analysis, or reporting of the trial.\u003c\/p\u003e\n\n\u003ch3\u003eWhich Patients Could Join\u003c\/h3\u003e\n\n\u003cp\u003eFemale and male adults could join if they had clinically node-negative breast cancer. \"Clinically node-negative\" means the armpit lymph nodes did not appear to contain cancer on examination. Their tumor stage had to be T1, T2, or T3. Tumor size was defined as T1 up to 20 mm, T2 from 21 to 50 mm, and T3 larger than 50 mm in the largest dimension. They also had to have one or two sentinel-node macrometastases, meaning cancer deposits larger than 2 mm in the largest dimension.\u003c\/p\u003e\n\n\u003cp\u003ePreoperative ultrasonography (ultrasound imaging) of the armpit was mandatory. Patients could not join if they had cancer spread outside the armpit region or distant metastases. They also could not join if they had a history of invasive breast cancer, or breast cancer in both breasts when one breast met exclusion criteria. Other reasons for exclusion were medical contraindications against radiation therapy or systemic treatment, or an inability to understand the trial information.\u003c\/p\u003e\n\n\u003cp\u003eAdditional micrometastases (deposits 2 mm or smaller) found on sentinel-node biopsy were allowed. Extracapsular extension was also allowed. Patients with suspicious but nonpalpable armpit lymph nodes on ultrasound were eligible even if a fine-needle aspiration confirmed cancer. After a protocol amendment in 2016, primary systemic treatment was allowed if the sentinel-node biopsy was performed before treatment started.\u003c\/p\u003e\n\n\u003ch3\u003eTreatment and Follow-Up\u003c\/h3\u003e\n\n\u003cp\u003eAfter sentinel-node biopsy, patients were randomly assigned by a computerized system. One group was assigned to completion axillary-lymph-node dissection. The other group was assigned to no further armpit surgery, called sentinel-node biopsy only.\u003c\/p\u003e\n\n\u003cp\u003eSome hospitals use intraoperative frozen section. This technique gives preliminary results of the sentinel-node biopsy during surgery. Depending on its use, completion dissection was performed either during the same surgery (intraoperative randomization) or during a second surgery (postoperative randomization).\u003c\/p\u003e\n\n\u003cp\u003eBreast-conserving surgery and mastectomy were both allowed. Negative surgical margins were mandatory, meaning no cancer cells at the edge of the removed tissue. Sites in Germany and Italy limited trial inclusion to patients having a mastectomy. This was because the ACOSOG Z0011 criteria had been implemented in those national guidelines.\u003c\/p\u003e\n\n\u003cp\u003eA sentinel node was defined as any lymph node that had taken up tracer material (blue dye or isotope). A node was also considered sentinel if it felt suspicious for cancer during intraoperative palpation. Lymph nodes that did not meet these criteria but were randomly removed during surgery were not classified as sentinel nodes. Metastases in such nonsentinel nodes did not lead to exclusion. The recommendations of the American Joint Committee on Cancer were used to assess the tissue samples.\u003c\/p\u003e\n\n\u003cp\u003eAdjuvant systemic treatment was recommended according to relevant national guidelines. It could consist of endocrine treatment or chemotherapy, or both, with or without targeted treatment. Whole-breast radiation therapy after breast-conserving surgery was mandatory. Indications for a radiation boost to the tumor bed, radiation therapy to the chest wall after mastectomy, and radiation therapy to regional lymph nodes followed national guidelines.\u003c\/p\u003e\n\n\u003cp\u003eQuality control of radiation therapy used source-data verification. The researchers compared data from the registered electronic case-report form with the actual radiation therapy plans. This was done for all patients who underwent randomization in Sweden or Denmark until May 31, 2019. The protocol did not specify particular radiation-therapy target volumes or doses. Therefore, the occurrence of protocol-prohibited radiation therapy was not assessed. The researchers evaluated how well the registered data on radiation to the breast or chest wall and to nodal target volumes (yes or no) matched the actual radiation therapy received. A detailed radiation-therapy review to evaluate the clinical significance of specific nodal target volumes and doses is ongoing.\u003c\/p\u003e\n\n\u003cp\u003eAt enrollment, all patients completed questionnaires about health-related quality of life and long-term arm complications. These included the EORTC Quality of Life Questionnaire (QLQ-C30), the breast cancer–specific QLQ-BR23 questionnaire, the EuroQol Group 5-Dimension questionnaire, and the Lymphedema Functioning, Disability, and Health Questionnaire. According to the protocol, patients will receive these questionnaires again after 1, 3, 5, and 10 years. No clinical measurements of lymphedema were conducted. One-year questionnaire data from a Swedish–Danish subpopulation were published in 2022. The 3-year data for the entire trial population are not yet available.\u003c\/p\u003e\n\n\u003cp\u003eFollow-up is being assessed with annual mammography for 5 years and another mammography after 10 years. Annual clinical examinations were mandatory at first. During the coronavirus disease 2019 pandemic, some clinical services were interrupted. The requirement for clinical visits was then replaced with the option of remote visits.\u003c\/p\u003e\n\n\u003ch3\u003eStudy Goals and Definitions\u003c\/h3\u003e\n\n\u003cp\u003eThe primary end point was changed from breast cancer–specific survival to overall survival in 2020. This change followed a recommendation from the independent data and safety monitoring board. Prespecified secondary end points were recurrence-free survival, breast cancer–specific survival, and patient-reported outcomes. The definition of recurrence-free survival follows the updated Standardized Definitions for Efficacy End Points (STEEP) criteria. It includes invasive recurrence and death.\u003c\/p\u003e\n\n\u003cp\u003eClinical noninferiority was defined as 5-year overall survival that was not worse by more than 2.5 percentage points when completion dissection was omitted. In numbers, this meant 94.0% in the dissection group and 91.5% in the sentinel-node biopsy–only group. This margin was intentionally small. It was half the margin used in the ACOSOG Z0011 trial. The researchers chose the smaller margin to increase clinical applicability and to be comparable with oncology trials evaluating systemic therapies.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers calculated that the trial needed 190 deaths to have 80% power with a one-sided alpha of 10%. The upper one-sided 90% confidence interval for the hazard ratio (sentinel-node biopsy only versus completion dissection) had to be below 1.44. Because of its clinical significance, the secondary end point of recurrence-free survival is being reported before the primary end point of overall survival. Statistical power for overall survival has not yet been reached.\u003c\/p\u003e\n\n\u003cp\u003eFor the secondary end point of recurrence-free survival reported here, the sample-size calculation was added to the protocol in June 2020. This calculation assumed that 5-year recurrence-free survival would be 90% in the dissection group, based on the safety analysis of May 2020. The threshold for the upper boundary of the confidence interval for the hazard ratio for recurrence or death stayed at 1.44. This resulted in a prespecified noninferiority margin of 4.1 percentage points. The researchers concluded that the trial would have sufficient power (80%) to conclude noninferiority once 190 events of recurrence or death had occurred.\u003c\/p\u003e\n\n\u003ch3\u003eHow the Analysis Groups Were Defined\u003c\/h3\u003e\n\n\u003cp\u003eAmong all patients who underwent randomization, the modified intention-to-treat population excluded those who withdrew informed consent within 21 days after randomization. This time point was before a potential second surgery with completion dissection. Patients who withdrew consent later had their data censored at the date of consent withdrawal.\u003c\/p\u003e\n\n\u003cp\u003eThe per-protocol population consisted of all patients who underwent armpit surgery according to their randomized group assignment. Patients who did not meet all inclusion criteria or who met any exclusion criteria at randomization were excluded from the per-protocol analyses. This was true even if the situation was discovered later.\u003c\/p\u003e\n\n\u003ch3\u003eStatistical Methods\u003c\/h3\u003e\n\n\u003cp\u003eThis analysis pertains to the prespecified secondary end point of recurrence-free survival. Descriptive clinical data are summarized for the two treatment groups. Categorical variables are presented as frequencies and percentages. Continuous variables are presented as means with standard deviations or as medians with ranges. For each variable, the numbers and percentages of patients with missing observations are presented.\u003c\/p\u003e\n\n\u003cp\u003eThe time to an event was calculated from the randomization date to the date of recurrence or death. For patients without an event, the time was calculated to the date of the last recorded visit. Recurrence-free survival was evaluated descriptively with Kaplan–Meier curves. The effect of omitting completion dissection on 5-year recurrence-free survival was assessed with a Cox proportional-hazards model. Final analyses were adjusted for the stratification factor of country. Hazard ratios (sentinel-node biopsy only versus completion dissection) are presented with 95% confidence intervals. The proportional-hazards assumption was evaluated with Schoenfeld residuals.\u003c\/p\u003e\n\n\u003cp\u003eThe per-protocol population was used for the main analysis. This choice was made because such a population is more conservative in a noninferiority analysis. The upper boundary of the confidence interval had to be below the noninferiority margin of 1.44 for the analysis of the hazard ratio for recurrence or death. A complementary one-sided noninferiority statistical test was performed. A P value of less than 0.025 was considered to indicate that the result was significantly below the noninferiority margin.\u003c\/p\u003e\n\n\u003cp\u003eClinically relevant subgroups were assessed in the per-protocol population. These subgroup analyses were not prespecified. Therefore, results are presented as hazard ratios with 95% confidence intervals that were not adjusted for multiple comparisons, without any formal statistical test. Sensitivity analyses were performed with a model adjusted for calendar period. Calendar period is a potential factor that may predict nonadherence to the assigned treatment. Sensitivity analyses were also performed in the modified intention-to-treat population. Another sensitivity analysis introduced the requirement that at least nine lymph nodes were removed in the dissection group, compared with the overall sentinel-node biopsy–only group.\u003c\/p\u003e\n\n\u003ch2 id=\"patients\"\u003eWho Took Part in the Study\u003c\/h2\u003e\n\n\u003cp\u003eTrial enrollment opened on January 31, 2015, and closed on December 31, 2021. Overall, 6,637 patients underwent screening at 67 sites internationally. A total of 2,766 patients underwent randomization.\u003c\/p\u003e\n\n\u003cp\u003eThe modified intention-to-treat population consisted of 2,624 patients. The per-protocol population consisted of 2,540 patients. Of these, 1,335 were assigned to undergo sentinel-node biopsy only and 1,205 to undergo completion axillary-lymph-node dissection.\u003c\/p\u003e\n\n\u003cp\u003eThe per-protocol population included 1,553 patients (61.1%) from Sweden, 803 (31.6%) from Denmark, 86 (3.4%) from Germany, 52 (2.0%) from Greece, and 46 (1.8%) from Italy.\u003c\/p\u003e\n\n\u003cp\u003eThe median follow-up was 46.8 months, with a range of 1.5 to 94.5 months. A total of 17 patients (9 in the sentinel-node biopsy–only group and 8 in the dissection group) left the trial before the reporting of radiation therapy was due.\u003c\/p\u003e\n\n\u003cp\u003eMost patients who remained in the trial until at least 1 year of follow-up underwent postoperative radiation therapy targeting regional lymph nodes. This was true for 1,192 of 1,326 patients (89.9%) in the sentinel-node biopsy–only group and 1,058 of 1,197 (88.4%) in the dissection group. All but 26 patients received some systemic treatment.\u003c\/p\u003e\n\n\u003cp\u003ePatients 65 years of age or older were well represented in the trial. There were 529 such patients (39.6%) in the sentinel-node biopsy–only group and 496 (41.2%) in the dissection group.\u003c\/p\u003e\n\n\u003ch3\u003ePatient and Tumor Characteristics\u003c\/h3\u003e\n\n\u003cp\u003eThe two groups were well balanced in their characteristics. The mean age was 61.0 years (standard deviation, 12.0) in the sentinel-node biopsy–only group and 60.9 years (standard deviation, 11.7) in the dissection group. The median age was 61 years in both groups, with a range of 20 to 94 years in the biopsy-only group and 34 to 90 years in the dissection group.\u003c\/p\u003e\n\n\u003cp\u003eAge distribution was similar between groups:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eYounger than 40 years: 37 patients (2.8%) in the biopsy-only group versus 32 (2.7%) in the dissection group\u003c\/li\u003e\n  \u003cli\u003e40 to 49 years: 220 (16.5%) versus 194 (16.1%)\u003c\/li\u003e\n  \u003cli\u003e50 to 64 years: 549 (41.1%) versus 483 (40.1%)\u003c\/li\u003e\n  \u003cli\u003e65 to 74 years: 334 (25.0%) versus 342 (28.4%)\u003c\/li\u003e\n  \u003cli\u003e75 years or older: 195 (14.6%) versus 154 (12.8%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMean tumor size was 24.4 mm (standard deviation, 15.5) in the biopsy-only group and 24.2 mm (standard deviation, 16.9) in the dissection group. Median tumor size was 20 mm in both groups. The range was 0.2 to 155 mm in the biopsy-only group and 1 to 155 mm in the dissection group.\u003c\/p\u003e\n\n\u003cp\u003eTumor stage distribution was similar:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eT1: 710 patients (53.2%) in the biopsy-only group versus 651 (54.0%) in the dissection group\u003c\/li\u003e\n  \u003cli\u003eT2: 552 (41.3%) versus 480 (39.8%)\u003c\/li\u003e\n  \u003cli\u003eT3: 73 (5.5%) versus 74 (6.1%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe number of removed sentinel lymph nodes was also similar. One or two sentinel nodes were removed in 934 patients (70.0%) in the biopsy-only group and 856 (71.0%) in the dissection group. Three or four were removed in 349 (26.1%) versus 303 (25.1%). More than four were removed in 52 (3.9%) versus 46 (3.8%). The mean was 2.1 sentinel nodes in both groups.\u003c\/p\u003e\n\n\u003cp\u003eOne sentinel-node macrometastasis was found in 1,143 patients (85.6%) in the biopsy-only group and 1,008 (83.7%) in the dissection group. Two macrometastases were found in 192 (14.4%) versus 197 (16.3%).\u003c\/p\u003e\n\n\u003cp\u003eThe number of axillary metastases differed between groups, as expected. The mean was 1.3 (standard deviation, 0.5) in the biopsy-only group and 2.3 (standard deviation, 3.0) in the dissection group. The median was 1 in both groups. The range was 1 to 5 in the biopsy-only group and 1 to 42 in the dissection group.\u003c\/p\u003e\n\n\u003cp\u003eBreast-conserving surgery was performed in 845 patients (63.3%) in the biopsy-only group and 775 (64.3%) in the dissection group. Mastectomy was performed in 490 (36.7%) versus 430 (35.7%).\u003c\/p\u003e\n\n\u003cp\u003eTumor histologic type was similar between groups. Invasive carcinoma of no special type was found in 997 patients (74.7%) in the biopsy-only group and 939 (77.9%) in the dissection group. Lobular carcinoma was found in 278 (20.8%) versus 226 (18.8%). Other types were found in 60 (4.5%) versus 40 (3.3%).\u003c\/p\u003e\n\n\u003cp\u003eNottingham histologic grade was also similar. Grade 1 tumors were found in 243 patients (18.2%) in the biopsy-only group and 211 (17.5%) in the dissection group. Grade 2 tumors were found in 786 (58.9%) versus 717 (59.5%). Grade 3 tumors were found in 298 (22.3%) versus 263 (21.8%). Grade data were missing for 8 patients (0.6%) versus 14 (1.2%).\u003c\/p\u003e\n\n\u003cp\u003eTumor subtype distribution was similar. ER-positive, HER2-negative tumors were found in 1,166 patients (87.3%) in the biopsy-only group and 1,034 (85.8%) in the dissection group. ER-positive, HER2-positive tumors were found in 84 (6.3%) versus 88 (7.3%). ER-negative, HER2-positive tumors were found in 23 (1.7%) versus 34 (2.8%). ER-negative, HER2-negative tumors were found in 57 (4.3%) versus 46 (3.8%). Subtype data were missing for 5 patients (0.4%) versus 3 (0.2%).\u003c\/p\u003e\n\n\u003cp\u003eThe Ki-67 proliferation index (a marker of how fast cancer cells divide) was similar. The mean was 24.6% (standard deviation, 17.2) in the biopsy-only group and 24.8% (standard deviation, 17.7) in the dissection group. The median was 20% in both groups, with a range of 1 to 98%. Ki-67 data were missing for 13 patients (1.0%) versus 18 (1.5%).\u003c\/p\u003e\n\n\u003ch2 id=\"findings\"\u003eKey Findings: Recurrence-Free Survival\u003c\/h2\u003e\n\n\u003cp\u003eOverall, 191 patients had recurrence or died during follow-up. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval, 87.5 to 91.9) in the sentinel-node biopsy–only group. It was 88.7% (95% confidence interval, 86.3 to 91.1) in the dissection group.\u003c\/p\u003e\n\n\u003cp\u003eThe country-adjusted hazard ratio for recurrence or death was 0.89 (95% confidence interval, 0.66 to 1.19). This result was significantly below the prespecified noninferiority margin (P\u0026lt;0.001). In plain language, the upper boundary of the confidence interval (1.19) was below the required threshold of 1.44. This means the simpler surgery was statistically shown not to be worse than the more extensive surgery.\u003c\/p\u003e\n\n\u003cp\u003eThe hazard ratio of 0.89 suggests a slightly lower risk of recurrence or death with sentinel-node biopsy only. However, the confidence interval crosses 1.0, which means this difference could be due to chance. The key finding is that the result fell within the acceptable noninferiority margin.\u003c\/p\u003e\n\n\u003ch2 id=\"subgroups\"\u003eResults in Specific Patient Groups\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers assessed clinically relevant subgroups in the per-protocol population. These subgroup analyses were not prespecified. Therefore, the results are presented as hazard ratios with 95% confidence intervals that were not adjusted for multiple comparisons. No formal statistical test was applied to these subgroup results. This means the subgroup findings should be interpreted with caution.\u003c\/p\u003e\n\n\u003cp\u003eSensitivity analyses were performed to test the strength of the main result. One analysis adjusted for calendar period as a potential factor that may predict nonadherence to the assigned treatment. Another analysis was performed in the modified intention-to-treat population. A third analysis introduced the requirement that at least nine lymph nodes were removed in the dissection group. These sensitivity analyses were designed to confirm that the main finding was robust.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis clinical trial provides robust evidence that omitting completion axillary-lymph-node dissection was safe in patients with clinically node-negative T1, T2, or T3 breast cancer and one or two sentinel-node macrometastases who received systemic treatment and radiation therapy according to national guidelines. The patients in this trial had clinically node-negative disease with one or two sentinel-node macrometastases. Most of them received radiation therapy that included the regional lymph nodes.\u003c\/p\u003e\n\n\u003cp\u003eThe finding matters because completion dissection carries a higher risk of long-term complications. The most important complication is lymphedema, which is swelling of the arm. In the earlier AMAROS trial, signs of lymphedema were twice as common after completion dissection as after axillary radiation therapy.\u003c\/p\u003e\n\n\u003cp\u003eThe SENOMAC trial was designed to address weaknesses of earlier trials. It enrolled 2,766 patients, which is a large number. It focused only on patients with sentinel-node macrometastases. It included groups that had been underrepresented before, such as patients having a mastectomy, patients with T3 tumors, and men. It also used a smaller noninferiority margin than the ACOSOG Z0011 trial, making the result more clinically meaningful.\u003c\/p\u003e\n\n\u003cp\u003eThe trial also collected detailed information about radiation therapy. Most patients in both groups received radiation therapy targeting regional lymph nodes. This is important because radiation to the lymph-node regions may help control any remaining cancer cells in the armpit.\u003c\/p\u003e\n\n\u003cp\u003eFor patients, the key message is that skipping the more extensive armpit surgery did not worsen recurrence-free survival at 5 years. This means patients may be able to avoid the risks of completion dissection without compromising their cancer outcomes. However, this applies to patients who meet the trial's criteria and who receive appropriate radiation therapy and systemic treatment.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eThe trial has several limitations that patients and doctors should consider.\u003c\/p\u003e\n\n\u003cp\u003eFirst, the median follow-up was 46.8 months, which is less than 4 years. The range was 1.5 to 94.5 months. Longer follow-up is needed to confirm that the results hold over time. The primary end point of overall survival has not yet reached statistical power. The recurrence-free survival result is being reported first because of its clinical significance.\u003c\/p\u003e\n\n\u003cp\u003eSecond, the subgroup analyses were not prespecified. This means the results in specific patient groups should be interpreted with caution. The confidence intervals were not adjusted for multiple comparisons, and no formal statistical test was applied.\u003c\/p\u003e\n\n\u003cp\u003eThird, the protocol did not specify particular radiation-therapy target volumes or doses. Therefore, the occurrence of protocol-prohibited radiation therapy was not assessed. A detailed radiation-therapy review to evaluate the clinical significance of specific nodal target volumes and doses is ongoing.\u003c\/p\u003e\n\n\u003cp\u003eFourth, no clinical measurements of lymphedema were conducted. The trial relied on patient-reported questionnaires. The 3-year questionnaire data for the entire trial population are not yet available.\u003c\/p\u003e\n\n\u003cp\u003eFifth, the coronavirus disease 2019 pandemic interrupted some clinical services. The requirement for annual clinical visits was replaced with the option of remote visits. This may have affected follow-up assessments.\u003c\/p\u003e\n\n\u003cp\u003eSixth, the trial included patients from five European countries. The results may not apply equally to patients in other regions with different treatment practices and guidelines.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased on this trial, patients with clinically node-negative breast cancer and one or two sentinel-node macrometastases may be offered sentinel-node biopsy only instead of completion axillary-lymph-node dissection. This decision should be made together with the treatment team.\u003c\/p\u003e\n\n\u003cp\u003ePatients considering this option should discuss the following points with their doctors:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003eWhether they meet the criteria used in this trial, including tumor stage and the number and size of sentinel-node metastases.\u003c\/li\u003e\n  \u003cli\u003eWhether radiation therapy targeting the regional lymph nodes is planned, since most patients in the trial received this treatment.\u003c\/li\u003e\n  \u003cli\u003eWhat systemic treatments (endocrine therapy, chemotherapy, or targeted therapy) are recommended based on their tumor characteristics.\u003c\/li\u003e\n  \u003cli\u003eThe risks and benefits of each surgical option, including the risk of lymphedema after completion dissection.\u003c\/li\u003e\n  \u003cli\u003eThe need for ongoing follow-up with annual mammography and clinical assessments.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe trial researchers are continuing to collect data. The primary end point of overall survival will be reported when enough events have occurred. A detailed radiation-therapy review is ongoing. The 3-year and 5-year quality-of-life and lymphedema questionnaire data will also be analyzed. These future results will provide more information about long-term outcomes and complications.\u003c\/p\u003e\n\n\u003cp\u003ePatients should also be aware that the trial was funded by the Swedish Research Council and others. The funders had no part in the design, performance, analysis, or reporting of the trial. The trial is registered at ClinicalTrials.gov with the number NCT02240472.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat did the SENOMAC trial find about skipping full armpit lymph node removal?\u003c\/h3\u003e\n\u003cp\u003eIn a trial of 2,766 patients with early breast cancer and cancer in one or two sentinel lymph nodes, skipping completion axillary-lymph-node dissection did not worsen outcomes. The estimated 5-year recurrence-free survival was 89.7% with sentinel-node biopsy only and 88.7% with full dissection. The result met the trial's strict definition of noninferiority, meaning the simpler surgery was statistically shown not to be worse.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible to join the SENOMAC trial?\u003c\/h3\u003e\n\u003cp\u003eAdults with clinically node-negative breast cancer (armpit nodes not appearing to contain cancer on examination) and tumor stage T1, T2, or T3 could join. They needed one or two sentinel-node macrometastases (cancer deposits larger than 2 mm). Preoperative ultrasound of the armpit was mandatory. Patients with cancer spread outside the armpit or distant metastases, or a history of invasive breast cancer, could not join.\u003c\/p\u003e\n\u003ch3\u003eWhat are the risks of completion axillary-lymph-node dissection?\u003c\/h3\u003e\n\u003cp\u003eCompletion axillary-lymph-node dissection removes many more lymph nodes from the armpit and can cause long-term problems, especially lymphedema—painful swelling of the arm caused by fluid buildup. In an earlier trial, signs of lymphedema were twice as common after completion dissection as after axillary radiation therapy. Skipping the more extensive surgery may allow patients to avoid these risks without compromising cancer outcomes.\u003c\/p\u003e\n\u003ch3\u003eWhat does the 5-year recurrence-free survival number mean?\u003c\/h3\u003e\n\u003cp\u003eRecurrence-free survival is the percentage of patients who have not had the cancer return or died within a certain period. In this trial, the estimated 5-year recurrence-free survival was 89.7% in the sentinel-node biopsy–only group and 88.7% in the dissection group. This means that after five years, about 90 out of 100 patients in each group had not had a recurrence or died.\u003c\/p\u003e\n\u003ch3\u003eWhat follow-up and treatments did patients in the trial receive?\u003c\/h3\u003e\n\u003cp\u003eMost patients in both groups received radiation therapy that included the lymph-node regions. All but 26 patients received some systemic treatment, such as endocrine therapy, chemotherapy, or targeted therapy. Follow-up included annual mammography for 5 years and another mammography after 10 years, plus annual clinical examinations. During the COVID-19 pandemic, some clinical visits were replaced with remote visits.\u003c\/p\u003e\n\u003ch3\u003eWhat are the limitations of the SENOMAC trial results?\u003c\/h3\u003e\n\u003cp\u003eThe median follow-up was 46.8 months (less than 4 years), so longer follow-up is needed. The primary endpoint of overall survival has not yet reached statistical power. Subgroup analyses were not prespecified and should be interpreted with caution. The protocol did not specify radiation-therapy target volumes or doses. No clinical measurements of lymphedema were conducted; the trial relied on patient-reported questionnaires. Results may not apply equally to other regions.\u003c\/p\u003e\n\u003ch3\u003eWhat should patients discuss with their doctors about skipping armpit surgery?\u003c\/h3\u003e\n\u003cp\u003ePatients considering sentinel-node biopsy only instead of completion dissection should discuss with their treatment team whether they meet the trial's criteria, including tumor stage and the number and size of sentinel-node metastases. They should also discuss whether radiation therapy targeting the regional lymph nodes is planned, what systemic treatments are recommended, the risks and benefits of each surgical option, and the need for ongoing follow-up.\u003c\/p\u003e\n\u003ch3\u003eI have early breast cancer with cancer in one or two sentinel lymph nodes — should I get a second opinion before agreeing to full armpit lymph node removal?\u003c\/h3\u003e\n\u003cp\u003eA second opinion can help when the choice is between sentinel-node biopsy only and completion axillary-lymph-node dissection. In a trial of 2,766 patients with clinically node-negative disease and one or two sentinel-node macrometastases, 5-year recurrence-free survival was 89.7% with biopsy only versus 88.7% with full dissection, meeting noninferiority. Most patients received radiation including the lymph-node regions. A second opinion can clarify whether you meet these criteria and whether nodal radiation and systemic treatment are planned. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases NEJM 2024\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e J. de Boniface, T. Filtenborg Tvedskov, L. Rydén, R. Szulkin, T. Reimer, T. Kühn, M. Kontos, O.D. Gentilini, R. Olofsson Bagge, M. Sund, D. Lundstedt, M. Appelgren, J. Ahlgren, S. Norenstedt, F. Celebioglu, H. Sackey, I. Scheel Andersen, U. Hoyer, P.F. Nyman, E. Vikhe Patil, E. Wieslander, H. Dahl Nissen, S. Alkner, Y. Andersson, B.V. Offersen, L. Bergkvist, J. Frisell, and P. Christiansen, for the SENOMAC Trialists' Group\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e The New England Journal of Medicine, April 4, 2024, Volume 390, Number 13, pages 1163-1175\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMoa2313487\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c\/strong\u003e ClinicalTrials.gov number NCT02240472\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Swedish Research Council and others\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919015493788,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-skipping-full-armpit-lymph-node-removal-is-safe-for-patients-with-node-negative-breast-cancer-and-one-or-two-sentinel-no-hero.png?v=1793341265","url":"https:\/\/diagnosticdetectives.com\/ar\/products\/skipping-full-armpit-lymph-node-removal-is-safe-for-patients-with-node-negative-breast-cancer-and-one-or-two-sentinel-node-macrometastases-who-receive-guideline-directed-treatment","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}