EORTC AMAROS TRIAL After Mapping of the Axilla: Radiotherapy or Surgery

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1 Dear participating members, First of all, the fellow workers of the AMAROS-trail would like to wish you a merry Christmas and every happiness and health in We are thankful for your great efforts last year and because of your enthusiastic participation, we reached the required accrual of 3458 patients. However, this will not bring the patients accrual to an end. Together with the Independent Data Monitoring Committee (IDMC) of the EORTC, we decided to increase the sample size. There are two reasons to increase the sample size: 1. The percentage of sentinel node positive patients is lower than hypothesized: 32% versus 40%, respectively. 2. The trial has a treatment non-compliance of 10%. To demonstrate the non-inferiority of axillary radiotherapy, we need 1394 patients with a positive sentinel node. Taking into account a prevalence of sentinel node biopsy positive (SNB+) patients of 32% and a treatment non-compliance of 10%, we need 4766 patients to guarantee 1394 complying SNB+ patients. Currently, the accrual is around 50 patients per month, so we expect to include this extra 1300 patients in two years. We are very much aware of the fact that this trial is already going on for a while, but we hope we can still rely on your full participation in these coming two years. Hopefully, the participation of Institute Curie in Paris and more members of the ALMANAC group in the United Kingdom will facilitate us to reach this number of patients in the near future. With this newsletter we want to take the opportunity to bring some important topics to your attention: Modifications in the AMAROS protocol o Enlargement of the allowed tumor size from 3 cm to 5 cm. o Increase of follow-up from 5 to 10 years. o No longer mandatory to locally treat ITC as SNB positive. Accrual status and Top 10 accruing hospitals. Compliance to shoulder function and quality of life. Axillary recurrence: a rare event? Cleaning up of the data of the first 2000 patients. Importance of correct reporting of the size of sentinel node metastasis We hope 2008 will become a fruitful year, Best wishes and kind regards, Emiel Rutgers, study coordinator and Marieke Straver, study monitor

2 Modifications in the AMAROS protocol Because the sample size of the AMAROS trial is going to be increased, the opportunity arose to immediately change some other topics in the AMAROS protocol. You will receive the new version of the protocol as soon as possible. Hereunder we will outline the modifications. Enlargement of the allowed tumor size It will be allowed to include patients with larger primary tumors, namely tumors smaller than 5 cm instead of tumors smaller than 3cm. Generally, it is considered to be safe to perform a sentinel node biopsy in tumors between 3 and 5 cm (American Society of Clinical Oncology (ASCO) guidelines). By enlarging the allowed tumor size to 5 cm, we reflect daily clinical practice and may slightly increase the sentinel node positive rate. It must be mentioned that an exclusion criteria for the AMAROS trial is previous treatment of breast cancer, so it is not allowed to give neoadjuvant chemotherapy or neoadjuvant hormonal therapy in patients participating in the AMAROS trial. One of the reasons for this remains the controversial thoughts about performing a sentinel node biopsy procedure after neoadjuvant chemotherapy. Increase of the follow up from five to ten year The follow up will be increased from 5 to 10 year for both the sentinel node negative as well as the sentinel node positive patients. Shoulder function and quality of life assessment will be done only at year 10 and not at year 6,7,8, and 9. There are several reasons to increase to follow up. Firstly, the primary endpoint of the trial, axillary recurrences, seem to be very rare. To reach the required 52 events to prove the non-inferiority of axillary radiation therapy we will presumably need a longer follow up. Secondly, the long term complications of radiation therapy may appear after several years, so a final comparison of the shoulder function and quality of life after 10 years seems to be reasonable. Thirdly, we prospectively collected a large group of patients treated with sentinel node biopsy and ten year results would be very valuable, also for the sentinel node negative patients. Treatment of Isolated Tumor Cells (< 0.2 mm) Investigators are increasingly reluctant to locally treat isolated tumor cells because of their low prognostic significance and low chance of becoming clinical evident. Regarding the TNM classification, isolated tumor cells can be considered as N0 patients and no further treatment is recommended solely based on the finding of isolated tumor cells. In the AMAROS protocol, patients with isolated tumor cells are considered as sentinel node positive and these patients are randomized between ALND and RT. But in the new version of the protocol you are allowed to omit axillary treatment in case of isolated tumor cells as only finding. The decision to not locally treat isolated tumor cells can be made per center. Though, it is very important that the presence of these isolated tumor cells is reported on the case report form, to allow us to analyse this group separately from lymph node negative cases. We will contact you as soon as the new version of the protocol will come into effect. 2

3 Accrual status and Top 10 accruing hospitals Institution by year Total 1 Firenze (Univ.Hosp) (12.7%) 2 Arnhem (Rijnstate Hosp) (11.2%) 3 Amsterdam (NKI AvL) ( 11.5%) 4 Drachten (Nijsmellinghe) (9.2%) 5 Apeldoorn(Gelre Hosp) (7.5%) 6 Eindhoven (Catharina Hosp) (6.1%) 7 Amstelveen (Amstelveen Hosp) (5.1%) 8 Delft (Reinier de Graaf Hosp) (4.8%) 9 Leiden (LUMC) (3%) 10 Haarlem (Kennemer gasthuis) (2.5%) 11 Amsterdam (AMC) (3%) 12 Utrecht (UMCU) (2.5%) 13 Den Haag (Westeinde MCH) (2.7%) 14 Ljubljana (Univ.Hosp) (3.5%) 15 Hardewijk(St.Jansdal ) (2.5%) 16 Lille (Centre Oscar Lambret) (2.5%) 17 Den Haag (Rode Kruis Hosp) (1.7%) 18 Turin (San Giovanni Hosp) (1.8%) 19 Grenoble (CHR) (1.7%) 20 Geneva, (Hop. Cantonal Un) (0.7%) 21 Roermond (Laurentius Hosp) (1.3%) 22 Cardiff (Univ. Wales) Groningen (AZG) (0.8%) 24 Nijmegen, (UMCN) (0.4%) 25 Den Haag (Bronovo Hosp) (0.5%) 26 Gdansk, (Medical Univ) (0.2%) 27 Istanbul (Marmara Univ. Hosp) (0.5%) 28 Haifa,(Rambam Med. Center) 2 2 (0.1%) 29 Den Haag (Leyenburg Hosp) (0.0%) 30 Hardenberg(Ropcke Zweers. Hosp) (0.0%) Total (100%) The golden node award 2008 This year the first golden node award for best performance in 2007 in the AMAROS trial will be distributed. The nominees were: 1. Leiden LUMC, 2. Cardiff University of Wales, 3. Haarlem Kennemergasthuis 4. Arnhem, Rijnstate ziekenhuis Golden Node We are very pleased to announce that this award will go to Rijnstate Hospital in Arnhem in the Netherlands, because they have already included 66 patients this year. We want to congratulate the whole team of the Rijnstate Hospital in Arnhem and they will receive the award together with a delicious surprise as soon as possible. 3

4 Compliance to follow up Assessment of morbidity is of paramount importance for the success of the AMAROS study. We want to assess the difference in morbidity between both treatment arms. Therefore, Quality of Life examination at 1, 2, 3, 5 and 10 years after treatment is necessary, as well as shoulder function evaluation at 1, 3, 5 and 10 year, restricted to those patients who received axillary treatment. In an important number of follow-up forms we are observing a backlog, especially the Quality of life forms at the 2 year time point. At this time point it is not necessary to assess the shoulder function, but quality of life evaluation is mandatory. Figure 1: Overall compliance to QoL and shoulder function evaluation forms. On the following page you can find the current status of your institute concerning compliance to follow up. We would kindly ask all institutes with compliance beneath 60% to evaluate their logistic approach to the data collection. These institutes will be contacted by the study monitor to find a way to increase their compliance. For instance, it could be supportive to keep the quality and life and shoulder function form in the patient file (perhaps it can be put in the files by your secretary or data managers), so it will catch your eye when the patient visits you. 4

5 Compliance to quality of life (QoL) and shoulder function evaluation per institution Institution QoL Baseline (%) QoL Followup (%) Shoulder function Baseline (%) Gelre Zkh / Lukas R. De Graaf Delft Catharina Zkh Eindh Ropcke Zweers Rode Kruis 'S Graven C.H.R. De Grenoble Centre Oscar Lambret N.K.I / A.V.L. A'Dam Umc St Radboud Nijm Umc Utrecht Univ Med Ctr Leiden Med Ctr Haaglanden Kennemer Haarlem UMCG Laurentius Roermond Amc Amsterdam Hc Uni.Geneve Gdansk-Med.Univ Univ Wales Coll Med S Giovanni Torino Pol Careggi Firenze Rambam Med. Center Slovenia/Inst. Of Onc Marmara Univ Hosp Harderwijk/Jansdal Arnhem/Rijnstate Den Haag/Bronovo Nij Smellinghe Zkh Amstelveen Shoulder function Follow-up (%) Red: <60% compliance 5

6 Axillary recurrences, a rare event? Does every axillary metastasis become clinical evident? What is the influence of adjuvant and hormonal therapy? Axillary recurrence is the primary endpoint of the AMAROS and therefore an important event in our study population. It seems to be that axillary recurrences are rare nowadays. A literature search for recently published studies results in an axillary recurrence rate of 0.4% (0-1.6%) in sentinel node positive patients treated with ALND (table 3). Even small series of patients with positive sentinel nodes who declined axillary dissection show a low rate of axillary recurrences (table 4). This low rate of axillary recurrences may reflect a low risk patient population and the effects of adjuvant radiotherapy, chemotherapy, and hormone therapy. Longer follow-up of these series will reveal the true axillary recurrence rate. Although, it is too early to evaluate the axillary recurrence rate in the AMAROS trial, we expect the axillary recurrence rate to be in the same range as currently published by others. Table 3 Axillary recurrences after SNB + and ALND Author No. of patients Median Follow-up (months) Badgewell (24-43) 1 (1.6%) Naik (1-74) 4 (0.35%) Jerrus (1-98) 0 (0%) Carcoforo (6-72) 0 (0) Takei (2-83) 2 (0.6%) Kostantiniuk (0-84) 2 (0.2%) Total (0.4%) Axillary recurrences No. (%) Table 4 Axillary recurrences after SNB + with no ALND Author No. of patients Median Follow-up (months) Guenther Fant (21-48) 0 Langer (12-64) 0 Jeruss (1-98) 0 Naik (1-72) 3 (1.4%) Hwang ( ) 0 Total (0.5%) Axillary recurrences No. (%) 6

7 Cleaning of the data of the first 2000 patients Recently, we started to clean up the data of the first 2000 patients. Especially at the beginning of the AMAROS trial the data collection and management was complicated. We realize that the implementation of three different versions of Case Report Forms was sometimes problematic and this caused a lot of work for the local datamanagers. Most institutions received a lot of queries in the last years and we are very thankful for the hard work of al local datamanagers. We will now start to review all CRF of the first 2000 patients, institution by institution. We will have a look at outstanding queries, see if they are still necessary and solve some queries ourselves in case a pathology report is added. During the time your institution will be evaluated and cleaned, you will receive a letter with our findings and only highly necessary queries. Still outstanding queries can be forgotten after the receipt of this letter. For the future we want to emphasize that is it of high importance to correctly report the size of sentinel node metastasis. Reporting micrometastases on pathology form 52 Reporting micrometastases it is important to distinguish between: 1. Macro-metastases > 2 mm. Box 05 and box 06 report by which technique this macrometastasis is found. There is no separate box to report you are dealing with a macrometastasis. Box 07 and 08 must be answered both with 0 (= no) 2. Micro- metastases mm. Box 05 and box 06 report by which technique this micrometastasis is found. Box 07 must be answered with 1(= yes) and box 08 must be answered with 0(= no). 3. Single tumor cells < 0.2 mm. Box 05 and box 06 report by which technique this single tumor cells are found. Box 07 must be answered with 0(= no) and box 08 must be answered with 1(=clusters) or 2 (= single cells). It is important that you are aware of the fact that when a pathologist talks speaks of micrometastasis in his pathology report it can either be a micrometastasis 0.2-2mm or a submicrometastasis < 0.2mm (isolated tumor cells). On the CRF it is important to distinguish between micrometastasis(0.2-2 mm) and isolated tumor cells ( <0.2 mm). Could you please enclose a copy of the original pathology report! 7

8 We thank you again very much for all your support and we wish you a merry Christmas and an excellent