AMAROS Trial Research Articles

The Role of Axillary Node Dissection in the Post Z0011 Era

Axillary lymph node dissection (ALND), once considered standard of care for all patients with invasive breast cancer, is now obsolete in patients with histologically negative sentinel lymph nodes (SLNs). Alternatives to ALND in patients with histologically positive SLNs are available after the ACOSOG Z0011 and AMAROS trials demonstrated no difference in locoregional recurrence, disease-free survival, or overall survival between SLN biopsy alone (ACOSOG Z0011) or with axillary radiotherapy (AMAROS) and ALND in women with clinical T1-2 invasive breast cancer and 1–2 positive SLNs treated with multimodality therapy, offering the opportunity to reduce the morbidity of treatment. In contrast, the MA.20 and EORTC 22922-10925 studies suggest that similar patient populations benefit from ALND and comprehensive nodal irradiation. Here, we will discuss the contemporary surgical management of clinically node-negative breast cancer patients with metastases in the SLNs.

P043. Specialist Masters Degree in Oncoplastic Breast Surgery: An update of student engagement and feedback

P043. Specialist Masters Degree in Oncoplastic Breast Surgery: An update of student engagement and feedback

Abstract P1-15-08: Tangential fields (TgF) breast radiotherapy (RT): Prospective evaluation of the dose distribution in the sentinel lymph node area (SLNa) as determined intra operatively by clip placement

Abstract Purpose: The coverage of axilla contents by radiation therapy (RT) is an important issue in the new era of minimal axillary surgery based on sentinel lymph node biopsy (SLNB). Data from recent trials demonstrated equivalent survival in breast cancer (BC) patients with 1-2 positive SLNs with or without axillary lymph node dissection (ALND). In a similar context, AMAROS trial showed that complete RT coverage of the axilla is a better option than ALND regarding the risk of arm lymphedema. Our recent data showed that axillary levels are underdosed when only tangential fields (TgFs) are used (Belkacemi et al, Ann Oncol 2013). We aimed to evaluate the dose distribution in the SLNa defined intra operatively by clips placement. This could be a important for patients with SLN involvement who have neither ALND nor RT to the axilla. Materials/Methods: Twenty-five patients have been prospectively included in this study. They had clips placement in the SLNa during the SLNB procedure. Breast dose was ranged between 40 to 50Gy in 15 to 25 fractions. Additional boost to the tumor bed of 10 or 16Gy was delivered in 21 patients. Level I-III and organs at risk were contoured using the RTOG contouring atlas. The SLNa was defined as 1.5 cm in diameter around the clips. Dose-volume-histograms were analyzed regarding the volumes receiving 95% or 50% of the prescribed dose. Percentages overlap between TgFs and SLNa volume were analyzed to define 3 groups: 100% overlap ("suitable group" with SNLa completely included in the TgF), > 50% overlap ("partially suitable group" with SLNa partially included in the TgF) and 0-49% overlap or completely outside the TgFs ("unsuitable group"). Results: The mean dose delivered to levels I, II, III and SLN area were 25, 5, 2 and 33Gy respectively. The volume covered by the 95%-isodose were respectively 2%, 0%, 0% and 4%. The average dose delivered to level I, II, III and SLN area were higher using High TgFs vs STgFs (38 vs 22Gy, p=0.004; 11 vs 3Gy, p=0.019; 5 vs 2Gy, p=0.003; 43 vs 31Gy,p=0.02), respectively. HTgFs covered better 50% of all axilla levels. Boost delivery and initial tumor site did not influence axilla coverage by the TgFs. The SNLa was totally or partially covered in 48% and 28% of patients, respectively. The mean dose delivered to 95% of the SNLa was only 22Gy using STgFs and 33Gy with the HTgFs. Using the STgFs, the SNLa was either totally (n=8/20) or partially (n=6/20) covered by > 50% of dose. Average dose was 46, 34 and 8Gy, respectively in the 3 groups. HTgFs allowed a complete coverage of the SLNa in all patients. Conclusion: In patients undergoing breast conservative therapy, TgFs provide a limited coverage of the SLNa. STgFs allowed total coverage of this area in less than half of the patients. Thus, SLNa should be delineated in patients who have only SLNB procedure. Some of these patients with nodal involvement without additional ALND could benefit from HTgFs irradiation or a better-personalized nodal RT using a dedicated nodal RT technique such that reported in AMAROS trial. The last allow better coverage of the axilla contents than TgFs. Citation Format: Yazid Belkacemi, Veronique Bigorie, Quiong Pan, Romain Bosc, Ryan Bouaita, Frederic Pigneur, Elias Assaf, Hakima Badaoui, Emmanuel Itti, Elie Calitchi. Tangential fields (TgF) breast radiotherapy (RT): Prospective evaluation of the dose distribution in the sentinel lymph node area (SLNa) as determined intra operatively by clip placement [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-08.

Abstract P1-15-09: Patterns of practice of regional node irradiation in the sentinel node biopsy era: Results of the nodal radiotherapy (NORA) survey. On behalf of the EORTC Breast Working Party of the Radiation Oncology Group (ROG)

Abstract Objective: Predicting the outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is a matter of debate, especially when it comes to the definition of regional nodal irradiation (RNI). This is even unclear in the framework of primary systemic therapy (PST). The aim of the NORA (NOdal RAdiotherapy) Survey was to examine the patterns of RNI practiced by European Radiation Oncology centers. Methods: A web questionnaire was distributed to EORTC centers, and responses were received during the period between July 2013-January 2014. Results: A total of 81 European and 3 non-European answers were analyzed. While 3D planning is performed in 81 (96%) of the centers for breast irradiation, nodal areas are delineated in only 51 (61%) of the centers. After breast conserving surgery (BCS), only 14 (17%) centers declared to treat systematically the internal mammary chain (IMC), when supraclavicular node RT (SCN-RT) is indicated. Extra-capsular extension (ECE) is the main factor impacting decision-making regarding IMC and axillary nodal RT (ALN-RT). Only half of the centers advocate SCN-RT for intermediate risk patients (1-3N+). For macro-metastatic SLN involvement, there was a significant impact of ECE on decision-making independently from the number of positive LNs. In the PST setting, only 49 (58%) centers take into account the histologic fibrotic changes of the axillary LNs in post-PST ypN0 patients with unknown pre-PST status. In ypN0 patients with inner and central BC, 32 (39%) and 23 (27%) centers centers indicate SCN-RT and IMC-RT, respectively. SCN-RT is delivered by 30, 44, 58, 67 centers in patients with ypN(i+), ypN(mi), 1-2N+ and > 3-4N+ disease, respectively. ALN-RT is indicated by in 25% of the centers in patients with ypN(mi) or 1-2N+. Older age > 70y was not considered as a limited factor for RNI. Discussion: The term of RNI is not uniformly defined in the literature. In the historic studies, RNI was dedicated to wide RT including whole lymphatic pathways of the breast. ALN and IMC RT indications have declined with the time during the last decades because of the risk of morbidity. However this practice is challenged by the recent RT trials that reported and increase of overall and distant metastatic survival with RNI and IMC delivery in high-risk N0 and inner-central tumors. In addition, AMAROS trial showed equivalence between axillary RT and ALND in SLN (mi+) patients. Taking these data altogether in the context of increased avoidance of ALND, future challenges should concern the multidisciplinary patients’ selection for RNI and better personalization of the lymphatic pathways RT according to the risk of locoregional and distant recurrences. Conclusions: The NORA Survey is unique by evaluating the impact of SLN status and PST on RNI decision-making. IMC RT is not frequently coupled to SCN-RT. ECE is the main factor impacting decision-making for RNI. Only 58% of the centers take fibrotic changes in the LNs into consideration in decision-making for RNI indications. Age is not considered as a limiting factor for prescribing RNI in Europe. Citation Format: Yazid Belkacemi, Orit Kaidar-Person, Philippe Poortmans, Mahmut Ozsahin, Maria-Clara Valli, Nicola Russell, Ian Kunkler, Julie Hermans, Abraham Kuten, Geertjan van Tienhoven, Helen Westenberg. Patterns of practice of regional node irradiation in the sentinel node biopsy era: Results of the nodal radiotherapy (NORA) survey. On behalf of the EORTC Breast Working Party of the Radiation Oncology Group (ROG) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-09.

How do the AMAROS trial results change practice?

How do the AMAROS trial results change practice?

Breast radiotherapy (RT) using tangential fields (TgF): a prospective evaluation of the dose distribution in the sentinel lymph node (SLN) area as determined intraoperatively by clip placement.

BackgroundRandomized trials have established that patients with limited involvement of sentinel lymph node (SLN) do not require axillary lymph node dissection (ALND). The similar outcome in patients with ≤2 positive SLN with or without additional ALND is attributed, in part, to tangential fields (TgF) RT. We evaluated the dose distribution in the SLN biopsy area (SLNBa) as determined intraoperatively by clips placement for radiotherapy (RT) optimization.MethodsThis prospective study included 25 patients who had breast conservation. Titanium clips were used intraoperatively to mark the SLNBa. All patients had 3D-conformal RT using standard (STgF) or high tangential fields (HTgF). Axillary levels, SLNBa, and organs at risk were contoured on a CT scan. Dose distribution and overlap between TgF and target volumes were analyzed.ResultsThe average doses delivered to axilla levels I-III and SLNBa were 25, 5, 2, and 33 Gy, respectively. The average dose delivered to SLNBa was higher using HTgF with better coverage of the axilla. Only 12 of 25 patients (48 %) had their SLNBa completely covered by the TgF. There was no impact of TgF size on ipsilateral lung dose. The mean heart dose delivered using STgF was lower than HTgF.ConclusionsIn the era of SLNB, axilla and SNLBa RT technique has to be standardized to deliver adequate dose. We recommend the use of HTgF or direct axillary RT techniques (such as in AMAROS trial) in patients with metastases in SLN without ALND completion, when only TgF are expected to cure potential residual disease in the axilla.

Abstract P1-01-19: Role of axillary clearance with tumor positive sentinel node in mastectomy group: Is the results of ACOSOG Z0011 trial adaptable to mastectomy patient?

Abstract Background: Recent data from ACOSOG Z0011 trial or AMAROS trial suggest that axillary lymph node dissection(ALND) may be unnecessary for patients with positive sentinel lymph node biopsy(SLNB) receiving breast conserving surgery(BCS) with irradiation. However, consensus statements and guidelines until recently recommended that patients with mastectomy and tumor positive sentinel node undergo completion ALND. In this preliminary study, we compared these patients who did not undergo ALND with the patients who received BCS with SLNB only and irradiation and we analyzed the locoregional recurrence rate to show no differences of outcomes between two groups. Method: We identified 6,163 women with invasive breast cancer who underwent surgical resection at the National Cancer Center (Goyang,Gyeonggi-do,Korea) between January 2000 to December 2011. Clinico-pathological data obtained from prospective collecting medical database of our institution were analyzed retrospectively. The mastectomy with positive SLNB group was 47 patients and BCS with positive SLNB and irradiation group was 172 patients. The primary end point was loco-regional recurrence rate. Result : Clinical and tumor characteristics were similar between two groups except T stage and receptor status. The mean tumor size was 5.5cm with mastectomy group and 3.5cm with BCS group. The median number of nodes removed was three. There was not a single case of locoregional recurrence in both groups. At a median follow-up of 53.5 months (last follow-up, May 2013), 5-year overall survival was 85.7% with mastectomy and 97.3% with BCS group. Conclusion : In our study, there was no case of locoregional recurrence as above. This results lend weight to the argument that SLNB without ALND may be reasonable management for selected patients with appropriate surgery and adjuvant systemic therapy. This study can be regarded as a preliminary study with a sufficient value despite of the prognosis showed some statistical differences between two groups. It resides in the difference of initial stage of patients of two groups. We will present additional data compared with the mastectomy with axillary clearance group at the meeting. Acknowledgement This work was supported by grant from the National Cancer Center Korea (1210331-2). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-19.

Final Results of AMAROS Trial

Final Results of AMAROS Trial

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

IntroductionMultifocal 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 MethodsFrom 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. ResultsThe 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. ConclusionIn 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.

493 Sentinel Node Identification Rate and Further Nodal Involvement in Patients with Multifocal Breast Cancer in the EORTC 10981-22023 AMAROS Trial

493 Sentinel Node Identification Rate and Further Nodal Involvement in Patients with Multifocal Breast Cancer in the EORTC 10981-22023 AMAROS Trial

Positive axillary sentinel lymph node: Is axillary dissection always necessary?

There is considerable interest in foregoing axillary dissection (AD) when the sentinel node (SN) is positive in early breast cancer, particularly when axillary involvement is minimal (micrometastases or isolated tumor cells). In fact, clinical practice has run ahead of the evidence, since recent population-based data indicate that AD is 'underused' in breast cancer patients when the SN is positive. Several trials are addressing the problem (IBCSG 23-01, ASCOG Z0011, EORTC AMAROS). Only Z0011 has published interim results, finding, after a median follow-up of 6.3 years, no differences in locoregional recurrence or regional recurrence between patients, with a positive SN, who received AD vs. no further axillary treatment. Our own retrospective study evaluated patients with micrometastases or isolated tumor cells in the SN who received no further axillary treatment. We found high five-year survival and low cumulative incidence of axillary recurrence, supporting the findings of Z0011 and justifying the increasingly common practice of foregoing AD in women with minimal SN involvement. It is important to sound a note of caution however: If axillary dissection is not always necessary in women with a positive axilla, it seems important to be able to reliably identify the patients at high risk of developing overt axillary disease who should receive elective AD. Ancillary analyses of the IBCSG 23-01 and AMAROS trials, still in follow-up, may be able to do this.

Sentinel Node Identification Rate and Nodal Involvement in the EORTC 10981-22023 AMAROS Trial

BackgroundThe randomized EORTC 10981-22023 AMAROS trial investigates whether breast cancer patients with a tumor-positive sentinel node biopsy (SNB) are best treated with an axillary lymph node dissection (ALND) or axillary radiotherapy (ART). The aim of the current substudy was to evaluate the identification rate and the nodal involvement.MethodsThe first 2,000 patients participating in the AMAROS trial were evaluated. Associations between the identification rate and technical, patient-, and tumor-related factors were evaluated. The outcome of the SNB procedure and potential further nodal involvement was assessed.ResultsIn 65 patients, the sentinel node could not be identified. As a result, the sentinel node identification rate was 97% (1,888 of 1,953). Variables affecting the success rate were age, pathological tumor size, histology, year of accrual, and method of detection. The SNB results of 65% of the patients (n = 1,220) were negative and the patients underwent no further axillary treatment. The SNB results were positive in 34% of the patients (n = 647), including macrometastases (n = 409, 63%), micrometastases (n = 161, 25%), and isolated tumor cells (n = 77, 12%). Further nodal involvement in patients with macrometastases, micrometastases, and isolated tumor cells undergoing an ALND was 41, 18, and 18%, respectively.ConclusionsWith a 97% detection rate in this prospective international multicenter study, the SNB procedure is highly effective, especially when the combined method is used. Further nodal involvement in patients with micrometastases and isolated tumor cells in the sentinel node was similar—both were 18%.

Role of Axillary Clearance After a Tumor-Positive Sentinel Node in the Administration of Adjuvant Therapy in Early Breast Cancer

PURPOSE The After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) phase III study compares axillary lymph node dissection (ALND) and axillary radiation therapy (ART) in early breast cancer patients with tumor-positive sentinel nodes. In the ART arm, the extent of nodal involvement remains unknown, which could have implications on the administration of adjuvant therapy. In this preliminary analysis, we studied the influence of random assignment to ALND or ART on the choice for adjuvant treatment. PATIENTS AND METHODS In the first 2,000 patients enrolled in the AMAROS trial, we analyzed the administration of adjuvant systemic therapy. Multivariate analysis was used to assess variables affecting the administration of adjuvant chemotherapy. Adjuvant therapy was applied according to institutional guidelines. Results Of 2,000 patients, 566 patients had a positive sentinel node and were treated per random assignment. There was no significant difference in the administration of adjuvant systemic therapy. In the ALND and ART arms, 58% (175 of 300) and 61% (162 of 266) of the patients, respectively, received chemotherapy. Endocrine therapy was administered in 78% (235 of 300) of the patients in the ALND arm and in 76% (203 of 266) of the patients in the ART arm. Treatment arm was not a significant factor in the decision, and no interactions between treatment arm and other factors were observed. Multivariate analysis showed that age, tumor grade, multifocality, and size of the sentinel node metastasis significantly affected the administration of chemotherapy. Within the ALND arm, the extent of nodal involvement remained not significant in a sensitivity multivariate analysis. CONCLUSION Absence of knowledge regarding the extent of nodal involvement in the ART arm appears to have no major impact on the administration of adjuvant therapy.

Technical aspects of the sentinel node biopsy in the EORTC AMAROS sentinel node trial.

Abstract Abstract #1006 Background: The AMAROS trial is a phase III study comparing axillary lymph node dissection (ALND) with axillary radiation therapy (ART) in patients with proven axillary metastasis by sentinel node biopsy (SNB). The main objective of the trial is to prove equivalent locoregional control and reduced morbidity for ART. The aim of this interim analysis was to analyze the technical aspects of the SNB.
 Methods: The first 2000 patients with operable unifocal invasive breast cancer (5-30 mm) and clinically negative lymph nodes enrolled in the AMAROS trial between 2001 and 2005 were analyzed. The 26 participating institutions have been site visited as part of the surgical quality assurance. SNB is performed using preoperative lymphoscintigraphy, blue dye and a gamma-ray detection probe. Patients with a negative sentinel node were not subjected to ALND or ART.
 Results: The SN identification rate was 97% (range per institute 89%- 99%), 33% (n=658) of the patients were SNB positive, 62% (n=1245) were SNB negative and 2%(n=32) had other outcomes (non-axillary, missing data). Median two sentinel nodes were removed in the SNB positive as well as the SNB negative group. In 17% (344) of the patients, non-blue and non radio-active nodes were removed during the sentinel node procedure, median 1 node. In 11 patients, these nodes were the only tumor positive nodes found. In the SNB positive group the incidence of macro-, micrometastasis and isolated tumor cells was 61% (389), 26% (164) and 13% (80), respectively. In the ALND arm, further nodal involvement was seen 47,5% , 21,4 % and 16,7%, respectively. There was no correlation between the size of metastasis and the tumor size, grade or histological subtype. Of the sentinel nodes 59% (1907/3259) were radioactive and blue, 33% (1087/3259) were only radioactive, 8 %(265/3259) were only blue. Non-visualization on lymphoscintigraphy was seen in 7.6%(152), in 78%(118) of these cases a sentinel node was found during surgery. At least one sentinel node was located in the axilla in 89%(1777), in the internal mammary chain in 5% (104) and infra/supraclavicular in 1%(15). The injection site was intra/peritumoral in 53% subcutane/intradermal over the tumor in 9% periareolair in 16%, a combination in 4%, missing data 17%. Sentinel nodes in the internal mammary chain were significantly correlated with a intratumoral injection technique.
 Conclusions: These results indicate that with a 97% detection rate in this prospective international multicenter study using the combination of radioactive tracer and blue dye, the sentinel node procedure is highly effective. Differences in injection site affect the finding of non axillary sentinel nodes. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1006.

329 POSTER EORTC 10981–22023 AMAROS trial: after mapping of the axilla radiotherapy or surgery? Current status

329 POSTER EORTC 10981–22023 AMAROS trial: after mapping of the axilla radiotherapy or surgery? Current status