Philip Meijnen

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.

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.

Immunohistochemical categorisation of ductal carcinoma in situ of the breast

The aim of this study is to analyse whether immunohistochemistry (IHC) applying a broad set of markers could be used to categorise ductal carcinoma in situ (DCIS) of the breast in distinct subgroups corresponding to the recently defined molecular categories of invasive carcinoma. Immunohistochemistry of pure DCIS cases constructed in tissue arrays was performed with 16 markers (oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Bcl-2, p53, Her2, insulin-like growth factor receptor, E-cadherin, epithelial membrane antigen (EMA), CA125, keratins 5/6, 14, 19, epidermal growth factor receptor, S100, and CD31). Results in 163 cases were analysed by unsupervised hierarchical clustering. Histological classification was performed by review of whole tissue sections and identified 36 well-, 55 intermediately, and 72 poorly differentiated DCISs. Unsupervised hierarchical cluster analysis categorised DCIS into two major groups that could be further subdivided into subgroups based on the expression of six markers (ER, PR, AR, Bcl-2, p53, and Her2). In the major predominantly ER/Bcl-2-positive (luminal) group, three subgroups (AR-positive (n=33), AR-negative (n=40), and mixed (n=34)) could be identified and included 34 well-differentiated DCISs. Within the major predominantly ER/Bcl-2-negative (nonluminal) group, a Her2-positive subgroup (n=34) was characterised by 31 poorly differentiated lesions. Eight triple-negative lesions, including one positive for keratin 5/6 and two positive for p53, were encountered. Intermediately differentiated DCIS shared a comparable IHC staining pattern with well-differentiated DCIS that was distinct from poorly differentiated DCIS (P<0.001). Ductal carcinoma in situ could be categorised by IHC into two major groups and five subgroups using six markers. Morphologically, intermediately differentiated DCIS seems to have more biological similarities with well-differentiated lesions as compared to poorly differentiated lesions.

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.

Clinical trials update of the European Organization for Research and Treatment of Cancer Breast Cancer Group

The present clinical trial update consists of a review of two of eight current studies (the 10981-22023 AMAROS trial and the 10994 p53 trial) of the European Organization for Research and Treatment of Cancer Breast Cancer Group, as well as a preview of the MIND-ACT trial. The AMAROS trial is designed to prove equivalent local/regional control for patients with proven axillary lymph node metastasis by sentinel node biopsy if treated with axillary radiotherapy instead of axillary lymph node dissection, with reduced morbidity. The p53 trial started to assess the potential predictive value of p53 using a functional assay in yeast in patients with locally advanced/inflammatory or large operable breast cancer prospectively randomised to a taxane regimen versus a nontaxane regimen.

Risk of invasion and axillary lymph node metastasis in ductal carcinoma in situ diagnosed by core-needle biopsy

The aim of the study was to assess the risk of invasion and axillary lymph node metastasis in patients with ductal carcinoma in situ (DCIS) diagnosed by preoperative core‐needle biopsy. The data were used to select criteria for patients in whom sentinel node (SN) biopsy might be indicated.

The effect of margins on the clinical management of ductal carcinoma in situ of the breast.

Complete excision is key to successful breast‐conserving treatment for patients diagnosed with ductal carcinoma in situ (DCIS). Patients with extensive DCIS should be considered the choice of mastectomy (followed by reconstruction), while for smaller DCIS breast‐conserving treatment should be performed by complete excision. This review reports on the effect of margins on the clinical management of patients with a diagnosis of DCIS. The role of preoperative imaging including MRI, surgical procedures, and pathology are described. J. Surg. Oncol. 2008;98:579–584.

Deviations from the planned dose during 48 hours of stepping source prostate brachytherapy caused by anatomical variations

BACKGROUND AND PURPOSE To determine the uncertainties in planned dose associated with catheter and organ movement during 48 hours of stepping source prostate brachytherapy. MATERIAL AND METHODS Pulsed-dose rate (PDR) prostate brachytherapy as a boost is given in 24 pulses every 2 hours, making the total treatment last 48 hours. The entire treatment is based on one plan, created on the planning CT (CT1). Two follow-up CTs (CT2 and CT3) were acquired; halfway through the treatment and at the end of treatment. On these repeat scans the catheters were reconstructed and PTV and OARs were delineated. The original treatment plan was calculated on the repeat CTs. Target coverage V(100%), D(90), dose to 2cm(3) (D2cm(3)) of the rectum and bladder and dose to 0.1cm(3) of the urethra were recorded from the recalculated DVHs. RESULTS On the two repeat CTs the V100% decreased -1.5% and -2.3% as compared to the planning CT. For the rectum D2cm(3), the average increase was 14.8% (CT1-CT2) and 17.3% (CT1-CT3). Increase in bladder D2cm(3) was on average 23.1% (CT1-CT2) and 24.8% (CT1-CT3). For the urethra D0.1cm(3) an average decrease of -2% (CT1-CT2) and -3.2% (CT2-CT3) was observed. CONCLUSIONS Changes in target coverage during treatment were small and considered clinically irrelevant. However, an overall increase in dose to the OARs was found as compared to the planned dose, which should be taken into account during treatment planning.

Multifocal Ductal Carcinoma In Situ of the Breast: A Contraindication for Breast-Conserving Treatment?

Multifocal ductal carcinoma in situ (DCIS) is usually considered a contraindication for breast-conserving treatment. Therefore, most patients will undergo mastectomy. In this issue of the Journal of Clinical Oncology, Rakovitch et al deserve credit for reporting the outcome of a large retrospective study of women with multifocal DCIS. Their patients were treated with breastconserving treatment, with or without radiotherapy. The authors concluded that even for multifocal DCIS, breast-conserving treatment can lead to low recurrence rates, provided that the disease is completely excised and that radiation is administered. They are, therefore, adding another point for discussion, because the optimal treatment for DCIS— even for unifocal disease—is often debated and the role of radiotherapy questioned. Although DCIS is considered a precursor for invasive cancer, not all lesions will progress to invasive malignant disease. Longterm follow-up of women treated with biopsy alone showed that progression to invasive breast cancer was observed in 39% for patients with low-grade DCIS. It is also important to note that approximately 50% of the patients with local failure have an invasive local recurrence and, therefore, harbor the risk of developing distant metastasis. Identification of patients at high risk for local recurrence is critical for improvement of treatment in patients diagnosed with DCIS. Mastectomy is associated with the best control rates, but because of its mutilating effect is considered overtreatment for in situ disease. Breast-conserving treatment followed by radiotherapy of the breast has become an acceptable alternative for smaller lesions and provides survival rates comparable to those achieved with mastectomy. The earlier findings from the Ontario Breast Screening Program that concluded that women with multifocal DCIS were three times more likely to receive a mastectomy compared with those DCIS without urged Rakovitch et al to determine whether or not multifocality is an independent risk factor for local recurrence. A total number of 615 patients treated with breast-conserving treatment (305 with radiotherapy, 310 without radiotherapy) for DCIS were reviewed, including 260 patients (42%) with multifocal lesions. Because there are many definitions of multifocality, the authors used the definition from Sikand et al, who considered multifocality a pathologic feature defined as more than one distinct focus of DCIS, with at least 5 mm of intervening healthy breast tissue confined to a single quadrant of the breast. Although we know that complete excision is key to successful treatment, there is not yet uniform agreement on the minimal margin width necessary to ensure a safe treatment or to omit additional radiotherapy. Unfortunately, this study does not provide any new information on this matter. The reliability of histologic margin assessment is mainly influenced by the growth pattern of DCIS within the breast and by the distance between tumor foci. With the described detailed pathologic assessment in this study, the likelihood of a false free margin can be kept low and should encourage the use of conserving treatment for DCIS. Rakovitch et al found a detrimental effect of multifocality on the local recurrence rate only of those patients who did not receive radiotherapy, as reflected in a 10-year local recurrence–free rate of 59% for patients with multifocal DCIS compared with 80% for those without (P .02). Radiotherapy after lumpectomy increased the local recurrence–free rate for multifocal DCIS, and no significant difference between multifocal and unifocal DCIS was observed (80% v87%, respectively; P .35). Of note is the finding that there was no significant association between multifocality and the development of invasive breast cancer. Their observations favor the choice of breast-conserving treatment, including radiotherapy, for multifocal DCIS. In addition, Rakovitch et al properly observed that studies on multifocal DCIS conducted before the era of mammographic screening are not comparable to the contemporary population of patients. Therefore, multifocal disease should not be confused with extensive disease because the latter mandates treatment by mastectomy to ensure clear surgical margins. In the study by Rakovitch et al, the preoperative assessment was performed by mammography because this is still considered the most optimal method of detection. Although the findings have the limitation of a retrospective study, the study by Rakovitch et al suggests that, for patients with multifocal disease limited to one quadrant, breast-conserving treatment by complete wide local excision and radiotherapy is not contraindicated. Because a randomized clinical trial will probably be never performed to answer the issue on multifocality, the findings of this study should not be ignored. To further improve the results, magnetic resonance imaging (MRI) could be helpful to select multifocal lesions suitable for safe breast-conserving treatment and those that are not. Esserman et al reported earlier in the Journal about the value of MRI for imaging DCIS. Further, the complementary role of MRI to mammography has recently been reported in a large prospective observational study that showed that MRI improved the ability to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 35 DECEMBER 1

Meta-analysis of sentinel node biopsy in ductal carcinoma in situ of the breast (Br J Surg 2008; 95: 547-554).

The Editors welcome topical correspondence from readers relating to articles published in the Journal. Responses should be sent electronically via the BJS website (www.bjs.co.uk). All letters will be reviewed and,if approved,appear on the website. A selection of these will be edited and published in the Journal. Letters must be no more than 250 words in length. Copyright