Ewing Sarcoma Family of Tumours (ESFT) are rare tumours, with metastatic spread at diagnosis in one out of three patients. Bone and/or bone marrow involvement strike markedly prognosis. Accurate initial staging is therefore fundamental for treatment adaptation. 18F-FDG PET/CT is the current modality for the evaluation of disease extension. The aim of this study is to assess the prospective value of FDG PET/CT compared to bone marrow cytology/biopsy (BMCB) staging in very high risk ESFT patients. Pediatric and adult patients from 15 French sarcomas referral centers with a diagnosis of extrapulmonary disseminated ESFT were prospectively included from 2017 to 2021, in the COMBINAIR3 phase II trial. This study aimed to evaluate a strategy combining dose dense induction chemotherapy, high dose consolidation and prolonged maintenance for these very high risk patients. All patients underwent baseline full body 18F-FDG PET/CT with centralized real-time imaging review and BMCB sampling at diagnosis consisting in both bone marrow cytology and biopsy (at least 2 different sites per patient). Patients management was similar wether bone spread was presenting as lytic or intra-medullarry lesion. We report here the baseline bone and bone marrow (BM) analysis. Out of 43 patients included (aged 6 to 47 years-old), 11 were positive on BMCB staging (cytology n=6, biopsy n=1, both n=4), all consistant with bone/BM extension defined on baseline 18F-FDG PET/CT: 6 had BM involvement on PET (5 of whom also had bone lesions), and 5 had bone involvement only. PET/CT identified metastatic spread to bone and/or BM in 35 patients (81%), including 24 with negative BMCB. Twenty-three had bone lesions, 11 had both bone and BM involvement and one had BM extension alone. Bone/BM involvement was confirmed either by lytic bone destruction on the CT-component or on MRI imaging. FDG PET/CT detects 3 times more bone/bone marrow lesions than bone marrow cytology/biopsy in the initial staging of very high risk Ewing Sarcoma. Our data suggest that BMCB sampling can be avoided in favor of non-invasive PET/CT staging.

The one-year follow-up of the RADIOPARP phase I trial, evaluating breast radiotherapy with Olaparib in TNBC patients, demonstrated an acceptable toxicity profile of this combination with few low-grade adverse events.

To report the Maximal Tolerated Dose (MTD) of Olaparib (O) administered with concurrent loco regional radiotherapy (RT) and evaluate the Dose-Limiting Toxicity (DLT). We conducted a single-institutional phase I study of olaparib and concurrent radiotherapy (RT) to the breast or chest wall and regional lymph nodes in patients with inflammatory, loco-regionally advanced or metastatic TNBC or Patient with Operated TNBC with residual disease. RT consisted of 50 Gy to the breast or chest wall and regional lymph nodes. This phase I dose-finding based on toxicity study was conducted in a sequential and adaptive Bayesian scheme, using the method of Time-to-event Continual Reassessment Method to determine the Maximum Tolerated Dose (MTD) of Olaparib associated with RT. The primary endpoint was Dose-Limiting Toxicity (DLT) occurring within 6 weeks after the end of the radiotherapy. Five dose levels are considered (25 mg, 50mg bid, 100mg bid, 150mg bid and 200mg bid daily). Twenty-four pts with performance status 0-1 were enrolled between 09/2017 and 11/2019. Of them, 21 underwent adjuvant RT-O because poor response to NAC, and 3 received preoperative RT–O because of progression after NAC. The patients' profile is given in the table. All patients received full course RT-O, as following: 4 pts at dose 50mg bid; 8 at 100x2; 7 at 150x2, and 5 at 200x2. No DLT was observed. Two pts (8.7%) experienced acute grade 3 dermatitis no grade 4 toxicities related to the RT were observed. The O-related toxicity was acceptable with mostly grade 1-2 symptoms. The only grade 3-4 hematological toxicity was lymphopenia in 11 cases. Dose of O was escalated to the target dose of 200 mgx2, without DLT. Further follow up is needed to evaluate the late toxicities.Abstract 50: TableCharacteristicsN0. (%)Age (years), median (range)46 (25-74)EE gradeII5 (22)III18 (78)Not done1Clinical T stageT14 (17)T214 (58)T34 (17)T41 (4)T4D1 (4)Clinical N stageN013 (54)N110 (42)N21 (4)Clinical M stageM020 (83)Mx4 (17) Open table in a new tab

Abstract Background and discussion: TNBC shares clinical and pathological features with hereditary BRCA1-related breast cancers, and in sporadic TNBC; dysregulation of BRCA1 has been frequently observed together with other defects in homologous recombination pathways. Preclinical studies have shown that breast cancer cell lines with a triple-negative phenotype are more sensitive to PARP1 inhibitors compared with non-TNBC cells. These lines of evidence provide a strong rationale for developing a new therapeutic approach to TNBC based on targeting the DNA-repair defects via PARP inhibition in these cancers that the most aggressive are the inflammatory, loco-regional advanced and metastatic breast cancer, as well as operated patients with residual disease (after primary systemic treatment-PST). The aim of this study is to determine the Maximal Tolerated Dose of Olaparib administered with concurrent loco regional RT in the previously described population of patients. Trial design: Olaparib (oral administration) will be administered at a starting dose of 50 mg bid. The other dose levels will be: 100 mg bid, 150 mg bid, 200 mg bid. The 25 mg bid dose will be included in the model to deal with unexpected high toxicity of the starting dose. Seven days prior to their first fraction of radiation therapy, patients will begin taking Olaparib at the assigned dose twice daily each day. All patients will receive radiotherapy on day 8 after the start of Olaparib of 50 Gy to the whole breast (or chest wall) with or withour lymph nodes (LN) in 25 daily fractions and 5 weeks. Eligibility Criteria: Women aged >18 years with histologically confirmed TNBC with loco-regional RT indication as : Non-operated: Inflammatory and/or advanced BC (T≥3 and/or N≥1) BC in progression during PST (containing anthracyclines or taxanes or the combination of both or containing platinium-based chemotherapy) or inoperable after PST. Non operable metastatic BC (all T, all N, M1; with evaluable disease). Or patients operated after PST and surgery with residual disease (non-pCR and pN+ disease, evaluable according to RECIST 1.1 criteria). Specific aims To assess the safety profile of Olaparib administered with concurrent RT. This study should be completed by a methylation study of BRCA1 and RAD51 promoters. Statistics Phase I dose-finding based on toxicity will be conducted in a sequential and adaptive Bayesian scheme, using the method of Time-to-event Continual Reassessment Method to determine the Maximum Tolerated Dose (MTD) of Olaparib associated with RT. The primary endpoint is Dose-Limiting Toxicity (DLT) occurring within 6 weeks after the end of RT (12 -13 weeks from the first drug intake, depending on the period of the radiotherapy treatment). Dose allocation will be centrally defined, based on DLT observed in all patients previously evaluated, by modeling the probability of DLT. An empiric model will be used for the dose-toxicity relationship. No intra-patient dose-escalation is permitted. No dose skipping in escalation is permitted. The MTD is defined as the dose associated with 25% of DLT. Target accrual: Twenty-four to 30 pts are expected to be enrolled. Contact: youlia.kirova@curie.fr Citation Format: Kirova YM, Ezzalfani M, Rodrigues M, Pierga J-Y, Salomon A, Stern M-H, Laki F, Mosseri V, Berger F, Neffrati S, Armanet S, Fourquet A. A phase I of olaparib with radiation therapy in patients with inflammatory, loco-regionally advanced or metastatic TNBC (triple negative breast cancer) or patient with operated TNBC with residual disease [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-04-01.

PurposeAbout one‐third of patients with rhabdomyosarcoma relapse despite appropriate treatment and experience a poor outcome. Little meaningful improvement in the outcome of this disease has been observed over the last 30 years. There is no clear international recommendation concerning the use of salvage chemotherapy at relapse. A retrospective multicenter analysis was therefore conducted to analyze the efficacy of various second‐line chemotherapy regimens in this setting.MethodsForty‐nine patients under the age of 18, with initially localized rhabdomyosarcoma, who relapsed after first complete remission, treated in three SFCE centers (Société Française des Cancers de l'Enfant) between 1995 and 2013, were analyzed.ResultsFirst relapse occurred after a median interval of 22 months and remained localized in 71.4% of cases. All patients received second‐line chemotherapy with an overall response to this salvage therapy of 39.1%. Best specific response rates were 73.3 and 42.9% for carboplatin/epirubicin/vincristine‐ifosfamide/vincristine/etoposide (CEV/IVE) (15 patients) and vincristine/irinotecan ± temozolomide (VI[T]) (seven patients), respectively. Overall, 40 patients (81.6%) were then eligible for delayed local treatment (surgery and/or radiotherapy) and 30 of them (61.2%) achieved second complete remission. After a median follow‐up of 5.4 years since the diagnosis of first relapse, 5‐year overall survival is 49.4% (95% CI: 34.2–64.6).ConclusionSalvage chemotherapy plays a central role in the management of patients with relapsed rhabdomyosarcoma. CEV/IVE and VI(T) regimens can be recommended as neoadjuvant chemotherapy before local treatment for patients with relapsed rhabdomyosarcoma. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

AimTo identify predictors for infiltrating carcinoma and lymph node involvement, before immediate breast reconstructive surgery, in patients with an initial diagnosis of extensive pure ductal carcinoma in situ of the breast (DCIS).Patients and methodsBetween January 2000 and December 2009, 241 patients with pure extensive DCIS in preoperative biopsy had underwent mastectomy. Axillary staging (sentinel node and/or axillary dissection) was performed in 92% (n = 221) of patients. Patients with micro-invasive lesions at initial diagnosis, recurrence or contralateral breast cancer were excluded.ResultsRespectively 14% and 21% of patients had a final diagnosis of micro-invasive carcinoma (MIC) and invasive ductal carcinoma (IDC). Univariate analysis showed that the following variables at diagnosis were significantly correlated with the presence of either MIC or IDC in the mastectomy specimen: palpable tumor (p = 0.002), high grade DCIS (p = 0.002) and detection of an opacity by mammography (p = 0.019). Axillary lymph node (ALN) involvement was reported in 9% of patients. Univariate analysis suggested that a body mass index higher than 25 (p = 0.007), a palpable tumor (p = 0.012) and the detection of an opacity by mammography (p = 0.044) were associated with an increased rate of ALN involvement.ConclusionSkin-sparing mastectomy and immediate breast reconstruction (IBRS) has become increasingly popular, especially for patients with extended DCIS of the breast. This study confirmed that extended DCIS is associated with a substantial risk of finding MIC or IDC on the surgical specimen but also ALN involvement. Adjuvant systemic treatment and/or radiotherapy could be indicated for some of these patients after the surgery. Patients should be informed of the rate of 1) complications associated to IBRS that will potentially delay the introduction of systemic or local therapy 2) complications associated to radiotherapy after IBRS.

BackgroundOrbital rhabdomyosarcoma (ORMS) is associated with an excellent survival rate greater than 85%, and is considered to be a favourable site for this tumour. Treatment is based on combination chemotherapy together with best local therapy, sometimes surgery but more often radiation therapy. Local therapy is associated with frequent and potentially severe late sequelae.DesignRetrospective hospital single-centre analysis.ParticipantsEighty-two patients treated in Institut Curie, Paris.MethodsTo define long-term status of survivors after localized ORMS, patients treated between 1975 and 2010 were analysed.Main Outcome MeasuresClinical structural and functional orbital, and general sequelae.ResultsMedian age at diagnosis was 6 years (range: 8 months-19 years), and median follow up was 8.5 years (range: 7 months-24 years). The 5-year globe conservation rate was 90.4%. Ophthalmic dysfunction was present in 79% of patients. Impaired visual acuity (VA), was present in 62% of patients; 38% of them had severe visual disability with VA<6/60. Late effects on orbitofacial structure were present in 39.8% of patients. Ocular or palpebral sequelae were present in 79% of survivors, mainly cataract (42%), ocular surface lesions such as keratoconjunctivitis (40%) and eyelid abnormalities (29%). General late effects were rare.ConclusionsThese data suggest that ocular and orbital late effects are frequent after treatment of ORMS, indicating the need for systematic long-term ophthalmologic follow up of these patients. Radiation therapy is an important part of the total burden of therapy.

Le traitement des rhabdomyosarcomes orbitaires (RMSO) comporte de la chimiothérapie associée au traitement local, basé sur la chirurgie ou principalement la radiothérapie. Ces derniers peuvent induire des effets tardifs notables peu décrits. Cette analyse rétrospective monocentrique a pour but de décrire les séquelles pour guider les décisions de décroissance thérapeutique pour cette tumeur de bon pronostic. 95 patients atteints de RMSO localisés, paraméningés (26%) ou non, ont été traités à l'Institut Curie entre 1975 et 2010, et 82 ont survécu avec suivi médian de 8,5 ans [0,6–24 ans]. L'âge médian au diagnostic était de 6 ans [0,7–19 ans]. Le taux de conservation oculaire à 5 ans est de 90% avec une atteinte ophtalmologique séquellaire chez 79%, principalement, cataracte (42%) et lésions cornéennes (40%). L'acuité visuelle résiduelle médiane est 4/10 [< 2/10–10/10]. Des séquelles orbito-faciales sont présentent chez 40% à type d'asymétrie (36%) et d'hypoplasie osseuse (35%) post radiques ou à la chirurgie mutilante (énucléation/exentération, 19%). Ces données suggèrent que les séquelles locales tardives sont fréquentes et nécessitent un suivi ophtalmologique prolongé. L'irradiation engendre une morbidité iatrogène notable.

OBJECTIVE To assess the visualisation of the left anterior descending (LAD) coronary artery on CT images used for breast radiation treatment planning. METHODS Delineation of the LAD artery was achieved for 25 breast patients by 1 radiologist and 1 radiation oncologist independently on two sets of images for each patient: one pre-operative CT scan using intravenous (IV) contrast media to determine the primary gross tumour volume (GTV) and one post-operative CT scan used for treatment planning. A Student's paired t-test was used to compare the number of CT slices in which the LAD was visible for each patient in the two series. Interpolations and extrapolations of the LAD volume were performed for the left-sided cases using a published heart atlas in order to report doses to the LAD structure. RESULTS There was a non-significant difference between the results with and without IV contrast media (p=0.34 for the radiologist; p=0.90 for the radiation oncologist). The visible LAD artery corresponded to a 30% portion (range 12-47%) of the interpolated structure. The maximum dose to the left artery varied widely, from 2.7 to 41.7 Gy, in the group of patients with left breast tumours. The largest values (>25 Gy) corresponded to those patients in whom the LAD artery distal extremity lay inside the breast fields. CONCLUSIONS With the current planning CT protocol, only one-third of the LAD artery could be objectively visualised. Contrast-enhanced imaging used for GTV delineation before the breast surgery did not improve the visualisation of the artery. ADVANCES IN KNOWLEDGE This study has revealed the lack of consistency that may be encountered when contouring heart vessels, thereby questioning the reliability of dose reporting.

BackgroundAlveolar soft part sarcomas (ASPS) are generally chemo- and radio-resistant mesenchymal tumours, with no standardized treatment guidelines. We describe the clinical behaviour of paediatric ASPS and compare these features to previously reported adult series.Patients and MethodsThe clinical data of 51 children and adolescents with ASPS, prospectively enrolled in or treated according to seven European Paediatric trials were analysed.ResultsMedian age was 13 years [range: 2-21]. Primary sites included mostly limbs (63%). IRS post-surgical staging was: IRS-I (complete resection) 35%, II (microscopic residual disease) 20%, III (gross residual disease) 18% and IV (metastases) 27%. Only 3 of the 18 evaluable patients (17%) obtained a response to conventional chemotherapy. After a median follow-up of 126 months (range: 9-240), 14/18 patients with IRS-I tumour, 10/10 IRS-II, 7/9 IRS-III and 2/14 IRS-IV were alive in remission. Sunitinib treatment achieved two very good partial responses in four patients. Ten-year overall survival (OS) and event free survival (EFS) was 78.07% and 62.8 +/- 7% respectively. Stage IV, size >5cm and T2 tumours had a poorer outcome, but only IRS staging was an independent prognostic factor.ConclusionsASPS is a very rare tumour frequently arising in adolescents and in the extremities, and chemo resistant. Local surgical control is critical. ASPS is a poorly chemo sensitive tumour. For IRS-III/IV tumours, delayed radical local therapies including surgery are essential. Metastatic patients had a poor prognosis but targeted therapies showed promising results. Pediatr Blood Cancer 2013;60:1826-1832. (c) 2013 Wiley Periodicals, Inc.

Introduction: Malignant sacrococcygeal (SC) germ cell tumours (GCT) may be diagnosed as primary pelvic tumour or malignant recurrence of foetal SC teratoma (FSCT) operated during the neonatal period. In order to evaluate the difference between these two populations, the authors report their experience with SC-GCT registered in the French TGM 95 protocol.Population and methods: The protocol comprised risk-adapted-chemotherapy (CT) followed by surgery. Standard risk (SR: localized tumour completely resected) had no adjuvant therapy. Intermediate-Risk (IR: localized tumour, incomplete or no initial surgery with alpha FP<15,000 ng/ml) received Vinblastine-Bleomycin-Cisplatin regimen; while High-Risk (HR: alpha FP > 15,000 ng/ml and/or metastases) received Etoposide-Ifosfamide-Cisplatin.Results: Fifty-seven patients with SC-GCT, aged 0-80 months (median 16), were registered between 1995 and 2005. Nineteen patients had secondary SC-GCT after FSCT. All patients received CT: 17 IR and 1 SR after reevolution; 39 HR (25 with metastases). 51 patients underwent delayed surgery, which was incomplete in 8 patients.Evolution: Seventy-two percent of the secondary SC-GCT had systematic biological follow-up. alpha FP increasing was the first presenting sign in 80% of the cases. Patients with secondary SC-GCT had a lower median alpha FP level at diagnosis, were less frequently classified as HR and received less CT. The two groups with secondary vs. primary SC-GCT had a statistically similar favourable outcome (Overall Survival: 93.8% vs. 86.2%; Event-Free Survival: 89.2 vs. 78.2%; p > 0.34 and > 0.32), respectively, but with less burden of therapy.Conclusions: SC-GCT has a good overall prognosis provided complete surgery is achieved and CT is administered to IR and HR patients. SC-GCT in patients followed by alpha FP after treatment for FSCT had less tumour extension than newly-diagnosed patients, probably because of earlier detection of the disease. (C) 2012 Elsevier Ltd. All rights reserved.

Background: In the INRG dataset, the hypothesis that any segmental chromosomal alteration might be of prognostic impact in neuroblastoma without MYCN amplification (MNA) was tested. Methods: The presence of any segmental chromosomal alteration (chromosome 1p deletion, 11q deletion and/or chromosome 17q gain) defined a segmental genomic profile. Only tumours with a confirmed unaltered status for all three chromosome arms were considered as having no segmental chromosomal alterations. Results: Among the 8800 patients in the INRG database, a genomic type could be attributed for 505 patients without MNA: 397 cases had a segmental genomic type, whereas 108 cases had an absence of any segmental alteration. A segmental genomic type was more frequent in patients >18 months and in stage 4 disease ( P <0.0001). In univariate analysis, 11q deletion, 17q gain and a segmental genomic type were associated with a poorer event-free survival (EFS) ( P <0.0001, P =0.0002 and P <0.0001, respectively). In multivariate analysis modelling EFS, the parameters age, stage and a segmental genomic type were retained in the model, whereas the individual genetic markers were not ( P <0.0001 and RR=2.56; P =0.0002 and RR=1.8; P =0.01 and RR=1.7, respectively). Conclusion: A segmental genomic profile, rather than the single genetic markers, adds prognostic information to the clinical markers age and stage in neuroblastoma patients without MNA, underlining the importance of pangenomic studies.

Background: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. Methods: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enroled in the prospective European INES trials. Results: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) ( P <0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P =0.0001, P =0.04 and P =0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival. Conclusion: In infants with stage 4s MYCN- non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.

Abstract Introduction: The aim of our study was to identify predictive factors of infiltrating carcinoma and lymph node involvement in patients with an initial diagnosis of extended pure ductal carcinoma in situ (DCIS) of the breast. Material and Methods: 241 patients diagnosed with extended pure ductal carcinoma in situ (DCIS) underwent treatment at the Institut Curie (2000-2009) consisting of mastectomy with or without immediate breast reconstruction (IMR). Axillary staging (sentinel node and/or standard procedure) was performed in 92% of patients. Patients with micro-invasive lesions at diagnosis, recurrence or contralateral breast cancer were excluded. Differences between groups were analysed by Chi-square or Fisher Exact tests for categorical variables and Student's t-test for continuous variables. Survival analyses were performed using KaplanMeier, with comparisons using the logrank test and hazard ratios estimated using the Cox proportional hazard model. P-values were considered significant when below 0.05. Results: Respectively 15% and 20%of patients had a final diagnosis of micro-invasive (MIC) and invasive ductal carcinoma (IDC). The median sizes of the DCIS and IDC were respectively 40mm [0-95] and 6mm [2-50] according to final histological assessment. Univariate analysis showed that the following variables at diagnosis were significantly correlated to the presence of either MIC or IDC in the mastectomy specimen; palpable tumor (p=0.02), high grade DCIS (p=0.02), detection of an opacity on mammography (p=0.01). Axillary lymph node involvement was reported in 9% of patients. In univariate analysis a BMI>25 (p=0.007), a palpable tumor (p=0.01), the detection of an opacity (p=0.04) were associated with an increase rate of lymph node involvement. A IMR was performed in 69% of patients. These patients were younger (P<0.00001), thinner (p=0.005), with fewer palpable tumors (p=0.01), and DCIS of lower grades (p=0.03) than patients denied of breast MRI. With a median follow-up of 30 months, 7 patients (3%) experience locoregional recurrence. In univariate analysis a BMI>25 (p=0.06), a palpable tumor (p=0.0004), an opacity (p=0.01) and extended microcalcifications (p=0.02) were associated with a higher rate of loco-regional recurrence. Immediate breast reconstruction was not a significant risk factor for loco-regional recurrence (p=0.31). Conclusion: Extended pure ductal carcinoma of the breast on preoperative biopsies is associated with a substantial risk of finding not only micro-invasive or invasive carcinoma on the mastectomy specimen but also axillary lymph node involvement. Some risk factors have been identified and should be used to exclude patients from immediate reconstruction surgery due to an increased risk of getting adjuvant systemic treatment and radiotherapy. Immediate breast reconstructive surgery was not associated with an increased risk of loco regional recurrence in our series. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-18.