P.H.M. Elkhuizen

Abstract OT2-1-03: Preoperative accelerated partial breast irradiation trial (PAPBI); defining radiosensitivity

Background and aim of the study: A.The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) is based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. B. By assessing tumor response to radiotherapy, an additional goal of the study is to develop a gene expression profile that predicts breast cancer radiosensitivity. This gene signature of breast radiosensitivity would further design optimal treatment strategies for individual breast cancer patients treated with BCT. Inclusion citeria : Patients 60 years or older with a cT To study radiosensit ivity, gene expression profiling from RNA and DNA isolated from biopsies (mRNA gene expression profiles, the miRNA expression profiles and the DNA copy number changes) taken of the tumor before radiotherapy and at time of surgery will be correlated with response to radiotherapy, defined as pathologic response at the time of the lumpectomy. Response of the tumor will be evaluated by MRI scan and PET (before radiotherapy and before surgery) and classical pathology. Endpoint : The main objective is to investigate the impact of a short fractionated schedule given preoperatively on cosmesis and breast fibrosis. Therefore, it is anticipated that the percentage of moderate or severe fibrosis will decrease from 27% as found in the boost arm of the EORTC boost-no boost trial to 15% (Collette et al EJC 2008). The total sample size of 120 patients will provide in excess of 80% power to detect the difference between the null hypotheses (a rate of fibrosis of 27%) and the alternative hypothesis (a rate of fibrosis of 15%) with an exact binomial test at 0.05 2-sided significance level. In addition, the 2-sided 95% confidence interval for the proportion of patients without local recurrence will extend 0.035 from the observed proportion for an expected proportion of 96%. An additional objective is to build a classifier (genomic or proteomic or any kind of molecular signature) to identify responders and non-responders. A total of 120 patients will be included in the study. The main analysis will include 60 patients in the training set and 60 in the validation set. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-03.

Abstract P5-14-05: Preoperative accelerated partial breast irradiation (PAPBI) trial: First results on acute toxicity, complications and cosmetic results

Background The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) was based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. Methods and materials Patients 60 years, T ≤ 3 cm, pN0(sn) (sentinel node procedure before RT), ductal carcinoma, unifocal on mammogram and MRI, undergo preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks); 6 weeks hereafter a wide local excision is performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). Results From May 2010- 2013, 58 patients (pts) were included. For 52 pts follow up information is available up to at least 3 months after treatment; mean age 67.2 years (59-80); mean tumor size 1.4 cm (0.4-3.2); differentiation grade: grade 1 (n = 22), grade 2 (n = 28), unknown n = 8; mainly ER+PR + neu- (n = 50). 34 pts received hormonal therapy, none chemotherapy. Toxicity Acute RT toxicity grade 0 (23) grade 1(8). Postoperative complications were noted in 9/52 pts (17%): 2/52 had direct post-operative bleeding needing re-surgery; 1/52 developed a hematoma two months after surgery, needing re-surgery; 6/52 (11.5%) had a postoperative wound infection and received oral antibiotics. Of these 6; 1 wound abscess needing re-surgery; 1 small fistula closing within ten months. In the first year 9/52 pts developed localized oedema at the RT side fading away within 9 months. 4/53 pts developed hematoma post surgery. Fibrosis and cosmetic outcome Fibrosis score at 1 year (n = 35): grade 0 (9), grade 1 (21), grade 2 (4) grade 3 (1). Cosmetic outcome was scored at 1 year (n = 28): excellent/good (25; 89%), fair (3;11%). At 2 years follow up: 10/11 patients excellent/good and 1/11 patient fair. Fibrosis was noted in a limited volume. One ipsi-lateral breast tumor recurrence was diagnosed after 12 months at skin entry of the biopsy tract. Discussion The short term results of this PAPBI trial are promising in terms of acute treatment-related toxicities, complications and cosmetic outcome. Our complication rate of 17% (11% wound infection, 8% hematoma) is comparable with others*. Excellent or good cosmetic outcome was found in 90%, improving over time. Longer follow-up and increasing patient inclusion are needed to evaluate treatment efficacy, cosmetic results and toxicity on the longer term. *Mukesh et al (Eur J Surg Oncol 2012; 648 pts Cambridge IMRT trial), 18% infection, 8% hematoma. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-05.

Abstract P4-02-01: 18F-FDG PET/CT for the assessment of locoregional lymph node involvement and radiotherapy indication in stage II-III breast cancer treated with neoadjuvant chemotherapy

Background: Risk for locoregional recurrence (LRR) in breast cancer depends on tumor size and on number and location of tumor-positive locoregional nodes. Postoperative irradiation of chest wall and/or locoregional nodes is advised in patients at high risk for LRR, but remains controversial in patients at intermediate risk. Because the number of tumor-positive axillary nodes in patients treated with neoadjuvant chemotherapy (NAC) can no longer be determined from the axillary lymph node dissection (ALND) and conventional staging of N3-disease with ultrasound is inaccurate, planning of radiotherapy in these patients is hampered. The aim of the present study was to assess the accuracy of 18F-FDG PET/CT for locoregional staging in stage II-III breast cancer patients scheduled for NAC. Second, we wished to assess the value of pre-chemotherapy PET/CT in estimating the risk for LRR and determining chest wall and/or locoregional radiotherapy indication, based on the detection of ≥4 FDG-avid axillary nodes or occult N3-disease. Methods: 278 patients underwent PET/CT of the thorax in prone position. Presence and number of FDG-avid nodes were evaluated, blinded for other diagnostic procedures. First, PET/CT findings were compared with histopathology before NAC (ultrasound with fine needle aspiration and/or sentinel lymph node biopsy (SLNB)) to determine the diagnostic accuracy for detection of axillary metastases and newly discovered N3-disease. Second, risk estimation and radiotherapy planning were evaluated with and without PET/CT. Conventional locoregional staging consisted of ultrasound with fine needle aspiration before, SLNB before, and ALND after NAC. Patients were classified as low-risk (cT2N0), intermediate-risk (cT0N1, cT1N1, cT2N1, and cT3N0), or high-risk (cT3N1, cT4, cN2-3, and (y)pN2-3) for LRR. Emphasis was on the number of patients upstaged to the high-risk group by PET/CT, requiring postoperative locoregional irradiation. Results: Sensitivity, specificity, positive predictive value, and negative predictive value in the detection of axillary metastases were 80%, 92%, 98%, and 53%, respectively. Occult lymph node metastases in the internal mammary chain and periclavicular area were detected in 17 (6%) and 25 (9%) patients, respectively. PET/CT detected occult N3-disease in 5 (11%) of 47 low-risk patients. In 116 intermediate-risk patients, PET/CT detected ≥4 FDG-avid nodes in 14 (12%) patients and occult N3-disease in 13 (11%) patients, upstaging 25 (22%) of intermediate-risk patients. In total, 30 (18%) of 278 low- and intermediate-risk patients were upstaged to the high-risk group, requiring chest wall and/or locoregional irradiation. Conclusion: In breast cancer patients scheduled for NAC, PET/CT renders pre-chemotherapy SLNB unnecessary in case of an FDG-avid axillary node and detects occult N3-disease in 15% of patients. Pre-chemotherapy PET/CT is a valuable tool for selection of high-risk patients who will benefit from locoregional radiotherapy. In our population, 18% of patients had an indication for locoregional irradiation based on PET/CT information, which was missed by conventional staging. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-02-01.