M. Donker

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial

BACKGROUND If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING EORTC Charitable Trust.

Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma In Situ: 15-Year Recurrence Rates and Outcome After a Recurrence, From the EORTC 10853 Randomized Phase III Trial

PURPOSE Adjuvant radiotherapy (RT) after a local excision (LE) for ductal carcinoma in situ (DCIS) aims at reduction of the incidence of a local recurrence (LR). We analyzed the long-term risk on developing LR and its impact on survival after local treatment for DCIS. PATIENTS AND METHODS Between 1986 and 1996, 1,010 women with complete LE of DCIS less than 5 cm were randomly assigned to no further treatment (LE group, n = 503) or RT (LE+RT group, n = 507). The median follow-up time was 15.8 years. RESULTS Radiotherapy reduced the risk of any LR by 48% (hazard ratio [HR], 0.52; 95% CI, 0.40 to 0.68; P < .001). The 15-year LR-free rate was 69% in the LE group, which was increased to 82% in the LE+RT group. The 15-year invasive LR-free rate was 84% in the LE group and 90% in the LE+RT group (HR, 0.61; 95% CI, 0.42 to 0.87). The differences in LR in both arms did not lead to differences in breast cancer-specific survival (BCSS; HR, 1.07; 95% CI, 0.60 to 1.91) or overall survival (OS; HR, 1.02; 95% CI, 0.71 to 1.44). Patients with invasive LR had a significantly worse BCSS (HR, 17.66; 95% CI, 8.86 to 35.18) and OS (HR, 5.17; 95% CI, 3.09 to 8.66) compared with those who did not experience recurrence. A lower overall salvage mastectomy rate after LR was observed in the LE+RT group than in the LE group (13% v 19%, respectively). CONCLUSION At 15 years, almost one in three nonirradiated women developed an LR after LE for DCIS. RT reduced this risk by a factor of 2. Although women who developed an invasive recurrence had worse survival, the long-term prognosis was good and independent of the given treatment.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023).

LBA1001 Background: Sentinel node biopsy (SNB) is standard in assessing axillary lymph node status for cN0 breast cancer patients. In case of a positive SNB, if treatment is advised, axillary lymph node dissection (ALND) is the current standard. Although ALND provides excellent regional control, it may give harmful side effects. Axillary radiotherapy (ART) instead of ALND was hypothesized to provide comparable regional control and less side effects. METHODS From 2001 to 2010, patients with cT1E2N0 primary breast cancer were enrolled in the EORTC phase III non-inferiority AMAROS trial. Patients were randomized between ALND and ART in case of a positive SNB. Primary endpoint was 5-year axillary recurrence rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), quality of life (QOL), shoulder movement and lymphedema at 1 and 5 years. RESULTS Of the 4,806 patients entered in the trial, 744 in the ALND-arm and 681 in the ART-arm had a positive SNB, 60% with a macrometastasis. The two treatment-arms were comparable regarding age, tumor size, grade, tumor type, and adjuvant systemic treatment. With a median follow up of 6.1 years, the 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND versus 1.03% (7/681) after ART. The planned non-inferiority test was underpowered because of the unexpectedly low number of events. The axillary recurrence rate after a negative SNB was 0.8% (25/3131). There were no significant differences between treatment arms regarding OS (5 yr estimates: 93.27% ALND, 92.52% ART, p=0.3386) and DFS (5 yr estimates: 86.90% ALND, 82.65% ART, p=0.1788). Lymphedema was found significantly more often after ALND (1yr: 40% ALND, 22% ART, p<0.0001 and 5yr: 28% ALND, 14% ART, p<0.0001). There was a nonsignificant trend toward more early shoulder movement impairment after ART. These findings were compatible with a trend in two QOL items in the arm symptom scale: swelling (ART better) and movement (ALND better). There were no other differences in QOL. CONCLUSION ALND and ART after a positive SNB provide excellent and comparable regional control. ART reduces the risk of short-term and long-term lymphedema compared to ALND. CLINICAL TRIAL INFORMATION NCT00014612.

Comparison of the sentinel node procedure between patients with multifocal and unifocal breast cancer in the EORTC 10981-22023 AMAROS Trial: Identification rate and nodal outcome

INTRODUCTION Multifocal breast cancer is associated with a higher risk of nodal involvement compared to unifocal breast cancer and the drainage pattern from multifocal localisations may be different. For this reason, the value of the sentinel node biopsy (SNB) procedure for this indication is debated. The aim of the current analysis was to evaluate the sentinel node identification rate and nodal involvement in patients with a multifocal tumour in the EORTC 10981-22023 AMAROS trial. PATIENTS AND METHODS From the first 4000 registered patients, 342 were identified with a multifocal tumour on histological examination and compared to a randomly selected control group of 684 patients with a unifocal tumour. The outcome of the SNB was assessed. RESULTS The sentinel node was identified in 96% of the patients with a multifocal tumour and in 98% of those with unifocal disease. In the multifocal group, 51% had a metastasis in the sentinel node compared to 28% in the unifocal group; and further nodal involvement after a positive sentinel node was found in 40% (38/95) and 39% (39/101) respectively. CONCLUSION In this prospective international multicentre study, the 96% detection rate indicates that the SNB procedure can be highly effective in patients with a multifocal tumour. Though the tumour-positive rate of the sentinel node was twice as high in the multifocal group compared to the unifocal group, further nodal involvement after a positive sentinel node was similar in both groups. This suggests that the SNB procedure is safe in patients with multifocal breast cancer.

Radioguided occult lesion localisation (ROLL) in breast-conserving surgery after neoadjuvant chemotherapy

BACKGROUND An important benefit of neoadjuvant chemotherapy, as compared to adjuvant chemotherapy, in breast cancer patients is down staging of the primary tumour, which allows for more breast-conserving surgery. When a tumour becomes non-palpable after this down staging, precise localisation of the original tumour bed is crucial to be able to perform breast-conserving surgery. Radioguided Occult Lesion Localisation with (99m)Technetium (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with non-palpable breast tumours. We modified this technique to use it in the neoadjuvant setting. The present analysis was performed to assess its feasibility and analyse the number of patients in which a mastectomy was correctly withheld using this technique. METHODS A retrospective analysis was performed for all patients who were treated with neoadjuvant chemotherapy between 2007 and 2010 in our institute and underwent breast-conserving surgery with the ROLL-(99m)Tc technique afterwards. The status of the margins and the weight of the resected specimen were assessed. RESULTS The median weight of the resected specimen in these 83 patients was 53 g (range: 11-204 g). Eleven of the 58 patients with residual disease revealed positive margins at pathological examination. However, in only 5 of those 11 patients a secondary mastectomy was indicated. This means that in 94% of all included patients a mastectomy was correctly withheld. CONCLUSION The ROLL-(99m)Tc technique is a feasible technique that can be used to perform breast-conserving surgery after neoadjuvant chemotherapy in a carefully selected group of patients.

Is axillary lymph node clearance required in node-positive breast cancer?

Although the majority of patients with breast cancer have clinically negative axillary nodes at preoperative assessment, around 15–20% of these women will have metastatic disease within the lymph nodes at operative sentinel node biopsy, and additional selective treatment to the axilla might be required. Local treatment to the axilla can include axillary node clearance or axillary radiotherapy. The recent results of the American College of Surgeons Oncology Group Z0011 trial suggested that some women would be safe from recurrence without further axillary treatment if they have less than three involved sentinel nodes, with no extracapsular spread. We review the evidence base for management of the axilla after detection of a positive sentinel node, discuss the evidence for why micrometastatic disease requires systemic but not axillary therapy, and present data suggesting that axillary irradiation for macrometastases gives equivalent control to axillary node clearance, but causes less morbidity such as lymphoedema. Ongoing trials will confirm whether any further therapy can be omitted for all patients with low volume, sentinel-node macrometastases.

Combined PET–CT and axillary lymph node marking with radioactive iodine seeds (MARI procedure) for tailored axillary treatment in node‐positive breast cancer after neoadjuvant therapy

The treatment of axillary lymph node metastases after neoadjuvant systemic therapy (NST) remains debatable and axillary lymph node dissection (ALND) is still the standard of care. Marking axillary lymph nodes with radioactive iodine seeds (MARI procedure) is accurate in restaging the axilla after NST (false‐negative rate 7 per cent). Here, the potential of tailored axillary treatment, determined by combining the results of PET–CT before NST with those of the MARI procedure after NST, was analysed.

Novel surgical technique to selectively remove metastatic axillary lymph nodes in breast cancer patients after neoadjuvant chemotherapy: The MARI procedure--Marking of the axilla with radioactive iodine seeds.

196 Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy cannot be accurately assessed. Therefore axilla-conserving therapy is not yet a benefit. We aimed to assess a new surgical method to evaluate the axillary response: the MARI procedure, which stands for Marking of the Axillary lymph node with Radioactive Iodine seeds. METHODS Prior to NAC, proven tumor-positive axillary lymph nodes were marked with a Iodine-125 seed. After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. RESULTS Tumor-positive axillary lymph nodes were successfully marked with Iodine-125 seeds in 68 patients. The marked lymph node (MARI-node) was surgically detected and selectively removed after NAC in all patients. The pathological response to chemotherapy in the MARI-node was indicative for the overall response in the additionally removed lymph nodes. In 47 patients the MARI-node contained residual disease (n=45 macrometastasis, n= 2 ITC). Thirty-five of them had macro- or micro metastases in the complementary axillary lymph node dissection specimen. In 21 patients the MARI-node was tumor negative. In 2 patients a macro metastasis was found in the additionally removed nodes, in 2 patients ITC were found and in the remaining 17 patients no residual tumor was found in the additionaly removed lymphnodes. (false negative rate of the MARI procedure: 9.5%). CONCLUSIONS This study shows that marking and selectively removing metastatic lymph nodes after NAC is feasible. The tumor-response in the marked lymph node may be used to tailor further axillary treatment, and herewith enabling axilla-conserving surgery after neoadjuvant chemotherapy.

Abstract PD06-06: Novel Surgical Technique To Assess the Response of Metastatic Axillary Lymph Nodes to Neoadjuvant Chemotherapy in Breast Cancer Patients

Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not assessed accurately, since SN biopsy either before or after NAC will not provide an accurate answer. Therefore a reliable axilla-conserving therapy is not yet a benefit. We developed a new surgical technique to evaluate the axillary nodal response by Marking of the Axillary lymph node with Radioactive Iodine seeds (= the MARI procedure) Method: Prior to NAC, tumor positive axillary lymph nodes were marked with a Iodine-125 seed under ultrasound guidance (the MARI node). After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether the pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. Results: In 44 patients who were scheduled for NAC the MARI procedure was attempted. In 42 patients the tumor-positive axillary lymph node was successfully marked with a radioactive Iodine-125 seed. Two patients appeared to have overt distant metastasis and did not undergo complete axillary dissection. Thus, in 40 patients the MARI node was selectively removed after NAC. In all these patients a complementary axillary lymph node dissection was performed. In 24 patients the MARI node contained a macrometastasis after NAC. In 4 patients only isolated tumor cells (ITC) were present in the MARI node. In 24 of these 28 patients further nodal involvement was found. More importantly: in 12 patients (=30%) no residual tumor was present in the MARI node (pathological complete response= pCR) and 10 of them also showed a pCR in the complementary axillary lymph node dissection. In one patient a macrometastasis, and in one, ITC were found in one of the additional nodes. Conclusion: In this study we present the first results of a new surgical technique to assess the response of metastatic lymph nodes in the context of NAC for breast cancer; the MARI procedure. We conclude that marking tumor-positive lymph nodes before NAC and selectively removing them after NAC is feasible. Moreover we report that this MARI node is indicative for the response to NAC in the other axillary nodes: in 30% of the treated patients an axillary pCR was found which was correctly indicated by a negative MARI node in all but one patient. Thus the MARI procedure will enable us to select patients in which axillary lymph node dissection can be avoided after NAC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-06.