Publications by authors named "Sophie Bockel"

19 Publications

  • Page 1 of 1

Imaging approaches and radiomics: toward a new era of ultraprecision radioimmunotherapy?

J Immunother Cancer 2022 07;10(7)

Department of Radiation Oncology, Gustave Roussy, Villejuif, France

Strong rationale and a growing number of preclinical and clinical studies support combining radiotherapy and immunotherapy to improve patient outcomes. However, several critical questions remain, such as the identification of patients who will benefit from immunotherapy and the identification of the best modalities of treatment to optimize patient response. Imaging biomarkers and radiomics have recently emerged as promising tools for the non-invasive assessment of the whole disease of the patient, allowing comprehensive analysis of the tumor microenvironment, the spatial heterogeneity of the disease and its temporal changes. This review presents the potential applications of medical imaging and the challenges to address, in order to help clinicians choose the optimal modalities of both radiotherapy and immunotherapy, to predict patient's outcomes and to assess response to these promising combinations.
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http://dx.doi.org/10.1136/jitc-2022-004848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260846PMC
July 2022

Practice changing data and emerging concepts from recent radiation therapy randomised clinical trials.

Eur J Cancer 2022 08 29;171:242-258. Epub 2022 Jun 29.

Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France; Université Paris-Saclay, Faculté de Médecine, F-94270, Le Kremlin Bicêtre, France; Université Paris-Saclay, Inserm U-1030, Laboratoire de Radiothérapie Moléculaire et d'Innovation Thérapeutique, F-94805, Villejuif, France. Electronic address:

Introduction: Oncology treatments are constantly and rapidly evolving. We aimed at highlighting the latest radiation therapy practice changing trials and emerging concepts, through an overview of recent randomised clinical trials (RCTs).

Materials And Methods: Requests were performed in the Medline database to identify all publications reporting radiation therapy RCTs from 2018 to 2021.

Results: Recent RCTs sustained the role of newer combinatorial strategies through radioimmunotherapy for early stage or metastatic lung cancer, newer pro-apoptotic agents (e.g. debio 1143 in locoregionally advanced head and neck squamous cell carcinoma) or nanoparticles (e.g. NBTXR3 in locally advanced soft-tissue sarcoma). High-tech radiotherapy allows intensifying treatments and gaining ground in some indications through the development of stereotactic body radiotherapy for example. First randomised evidence on personalised radiation therapy through imaging-based (FDG positron emission tomography-computed tomography for lung cancer or early stage unfavourable Hodgkin lymphoma, PMSA positron emission tomography-computed tomography or magnetic resonance imaging for high-risk prostate cancer) or biological biomarkers (PSA for prostate cancer, HPV for head and neck cancer, etc) were conducted to more tailored treatments, with more favourable outcomes. Patients' quality of life and satisfaction appeared to be increasing aims. RCTs have validated (ultra)hypofractionated schemes in many indications as for breast, prostate or rectal cancer, resulting in equivalent outcomes and toxicities, more convenient for patients and favouring shared decision making.

Conclusion: Radiation therapy is a dynamic field of research, and many RCTs have greatly impacted therapeutic standards over the last years. Investments in radiotherapy research should facilitate the transfer of innovation to clinic.
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http://dx.doi.org/10.1016/j.ejca.2022.04.038DOI Listing
August 2022

A Predictive Clinical-Radiomics Nomogram for Survival Prediction of Glioblastoma Using MRI.

Diagnostics (Basel) 2021 Nov 4;11(11). Epub 2021 Nov 4.

Department of oncology, Gustave Roussy, Université Paris Saclay, 94805 Villejuif, France.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adult patients with a median survival of around one year. Prediction of survival outcomes in GBM patients could represent a huge step in treatment personalization. The objective of this study was to develop machine learning (ML) algorithms for survival prediction of GBM patient. We identified a radiomic signature on a training-set composed of data from the 2019 BraTS challenge (210 patients) from MRI retrieved at diagnosis. Then, using this signature along with the age of the patients for training classification models, we obtained on test-sets AUCs of 0.85, 0.74 and 0.58 (0.92, 0.88 and 0.75 on the training-sets) for survival at 9-, 12- and 15-months, respectively. This signature was then validated on an independent cohort of 116 GBM patients with confirmed disease relapse for the prediction of patients surviving less or more than the median OS of 22 months. Our model insured an AUC of 0.71 (0.65 on train). The Kaplan-Meier method showed significant OS difference between groups (log-rank = 0.05). These results suggest that radiomic signatures may improve survival outcome predictions in GBM thus creating a solid clinical tool for tailoring therapy in this population.
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http://dx.doi.org/10.3390/diagnostics11112043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624566PMC
November 2021

A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes.

Acta Neuropathol Commun 2021 10 29;9(1):174. Epub 2021 Oct 29.

Department of Neuropathology, GHU Paris - Psychiatry and Neuroscience, Sainte-Anne Hospital, 1, rue Cabanis, 75014, Paris, France.

A novel histomolecular tumor of the central nervous system, the "intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive" has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient's death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology "IMT, FET-CREB fusion-positive", and that further series of cases are needed to better characterize them.
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http://dx.doi.org/10.1186/s40478-021-01278-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555238PMC
October 2021

Pulse-dose-rate interstitial brachytherapy in anal squamous cell carcinoma: clinical outcomes and patients' health quality perception.

J Contemp Brachytherapy 2021 Jun 18;13(3):263-272. Epub 2021 May 18.

Brachytherapy Unit, Radiation Oncology Department, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

Purpose: To examine clinical outcomes and quality of life of patients with anal squamous cell carcinoma treated with interstitial pulsed-dose-rate brachytherapy (PDR-BT) with a boost to residual tumor after external radiotherapy.

Material And Methods: Medical records of patients receiving a brachytherapy boost after radiotherapy for anal squamous cell carcinoma in our Institute between 2008 and 2019 were retrospectively reviewed. After receiving pelvic irradiation ± concurrent chemotherapy, patients received PDR-BT boost to residual tumor, in order to deliver a minimal total dose of 60 Gy. Patients' outcomes were analyzed, with primary focus on local control, sphincter preservation, morbidity, and quality of life.

Results: A total of 42 patients were identified, included 24, 13, and 5 patients with I, II, and III tumor stages, respectively. Median brachytherapy (BT) dose was 20 Gy (range, 10-30 Gy). Median dose per pulse was 42 cGy (range, 37.5-50 cGy). With median follow-up of 60.4 months (range, 5.4-127.4 months), estimated local control and colostomy-free survival rates at 5 years were both 88.7% (95% CI: 67.4-96.4%). The largest axis of residual lesion after external beam radiation therapy (EBRT) and poor tumor shrinkage were associated with more frequent relapses ( = 0.02 and = 0.007, respectively). Out of 40 patients with more than 6 months follow-up, only one experienced severe delayed toxicity (fecal incontinence). Health quality perception was very good or good in 20 of 22 (91%) patients, according to their replies of quality-of-life surveys. A total dose ≥ 63 Gy was associated with higher number of anorectal grade 1+ toxicities ( = 1.5 vs. = 0.61, = 0.02).

Conclusions: In this cohort of 42 patients with mainly I and II tumor stages, PDR-BT boost allowed for local control in 88.7% of patients, with only one grade 3 anorectal toxicity.
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http://dx.doi.org/10.5114/jcb.2021.106247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170522PMC
June 2021

Venezia applicator with oblique needles improves clinical target volume coverage in distal parametrial tumor residue compared to parallel needles only.

J Contemp Brachytherapy 2021 Feb 18;13(1):24-31. Epub 2021 Feb 18.

Radiation Therapy Department, Gustave Roussy, Villejuif, France.

Purpose: Residual distal parametrial involvement after radiochemotherapy is a true challenge for brachytherapists since the width and asymmetry of high-risk clinical target volume (HR-CTV) are difficult to cover properly with a standard implant.

Material And Methods: Dosimetric plans of five patients treated with Venezia advanced gynecological applicator at our institution were reviewed. For each patient, we compared the original plan with a new plan where oblique needles were removed and re-optimized manually. Optimization process was halted when EQD2 D HR-CTV reached 90 Gy, when one hard constraint to organs at risk (OARs) was reached according to the EMBRACE II protocol, or when dose-rate of one of OARs exceeded 0.6 Gy/h.

Results: Tumors were large; median HR-CTV volume was 64 cc and median distance between tandem and outer contour of HR-CTV was 40 mm. For the five patients, HR-CTV EQD2 D was superior in the plan using oblique needles, with a median difference of 6.5 Gy (range, 1.7-8.5 Gy). Median D HR-CTV and intermediate-risk CTV (IR-CTV) were significantly increased with oblique needles: 85.9 Gy (range, 83.2-90.3 Gy) vs. 81.5 Gy (range, 77.4-84 Gy), and 68.7 Gy (range, 66.3-72.3 Gy) vs. 67 Gy (range, 64.3-69.1 Gy), = 0.006 for both. There were no significant differences in the dose to OARs. Plans with only parallel needles had less favorable dose distribution, with cold spots on the outer parametria and higher vaginal activation to compensate parametrial coverage in its inferior part.

Conclusions: Venezia applicator permits reproducible application to increase CTV coverage in patients with distal parametrial tumor residue during brachytherapy, while maintaining acceptable dose to OARs.
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http://dx.doi.org/10.5114/jcb.2021.103583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117708PMC
February 2021

Pulsed Dose Rate Brachytherapy of Lip Carcinoma: Clinical Outcome and Quality of Life Analysis.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Radiation Oncology Department, Gustave Roussy Cancer Campus, Université Paris-Saclay, 114 rue Edouard Vaillant, 94800 Villejuif, France.

Purpose: Lip carcinoma represents one of the most common types of head and neck cancer. Brachytherapy is a highly effective therapeutic option for all stages of lip cancers. We report our experience of pulsed dose rate brachytherapy (PDR) as treatment of lip carcinoma.

Methods And Materials: this retrospective single center study included all consecutive patients treated for a lip PDR brachytherapy in our institution from 2010 to 2019. The toxicities and outcomes of the patients were reported, and a retrospective quality of life assessment was conducted by phone interviews (FACT H&N).

Results: From October 2010 to December 2019, 38 patients were treated in our institution for a lip carcinoma by PDR brachytherapy. The median age was 73, and the majority of patients presented T1-T2 tumors (79%). The median total dose was 70.14 Gy (range: 60-85 Gy). With a mean follow-up of 35.4 months, two patients (5.6%) presented local failure, and seven patients (19%) had lymph node progression. The Kaplan-Meier estimated probability of local failure was 7.2% (95% CI: 0.84-1) at two and four years. All patients encountered radiomucitis grade II or higher. The rate of late toxicities was low: three patients (8.3%) had grade II fibrosis, and one patient had grade II chronic pain. All patients would highly recommend the treatment. The median FACT H&N total score was 127 out of 148, and the median FACT H&N Trial Outcome Index was 84.

Conclusions: This study confirms that an excellent local control rate is achieved with PDR brachytherapy as treatment of lip carcinoma, with very limited late side effects and satisfactory functional outcomes. A multimodal approach should help to improve regional control.
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http://dx.doi.org/10.3390/cancers13061387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003123PMC
March 2021

Image-Guided Brachytherapy for Salvage Reirradiation: A Systematic Review.

Cancers (Basel) 2021 Mar 11;13(6). Epub 2021 Mar 11.

Department of Radiation Oncology, Gustave Roussy, Paris-Saclay University, 94800 Villejuif, France.

Background: Local recurrence in gynecological malignancies occurring in a previously irradiated field is a challenging clinical issue. The most frequent curative-intent treatment is salvage surgery. Reirradiation, using three-dimensional image-guided brachytherapy (3D-IGBT), might be a suitable alternative. We reviewed recent literature concerning 3D-IGBT for reirradiation in the context of local recurrences from gynecological malignancies.

Methods: We conducted a large-scale literature research, and 15 original studies, responding to our research criteria, were finally selected.

Results: Local control rates ranged from 44% to 71.4% at 2-5 years, and overall survival rates ranged from 39.5% to 78% at 2-5 years. Grade ≥3 toxicities ranged from 1.7% to 50%, with only one study reporting a grade 5 event. Results in terms of outcome and toxicities were highly variable depending on studies. Several studies suggested that local control could be improved with 2 Gy equivalent doses >40 Gy.

Conclusion: IGBT appears to be a feasible alternative to salvage surgery in inoperable patients or patients refusing surgery, with an acceptable outcome for patients who have no other curative therapeutic options, however at a high cost of long-term grade ≥3 toxicities in some studies. We recommend that patients with local recurrence from gynecologic neoplasm occurring in previously irradiated fields should be referred to highly experienced expert centers. Centralization of data and large-scale multicentric international prospective trials are warranted. Efforts should be made to improve local control while limiting the risk of toxicities.
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http://dx.doi.org/10.3390/cancers13061226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999189PMC
March 2021

Systematic Screening of COVID-19 Disease Based on Chest CT and RT-PCR for Cancer Patients Undergoing Radiation Therapy in a Coronavirus French Hotspot.

Int J Radiat Oncol Biol Phys 2021 07 17;110(4):947-956. Epub 2021 Feb 17.

Department of Radiation Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, France; Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Gustave Roussy, Villejuif, France. Electronic address:

Purpose: Patients with cancer are presumed to be more vulnerable to COVID-19. We evaluated a screening strategy combining chest computed tomography (CT) and reverse-transcription polymerase chain reaction (RT-PCR) for patients treated with radiation therapy at our cancer center located in a COVID-19 French hotspot during the first wave of the pandemic.

Methods And Materials: Chest CT images were proposed during radiation therapy CT simulation. Images were reviewed by an expert radiologist according to the COVID-19 Reporting and Data System classification. Nasal swabs with RT-PCR assay were initially proposed in cases of suspicious imaging or clinical context and were eventually integrated into the systematic screening. A dedicated radiation therapy workflow was proposed for COVID-19 patients to limit the risk of contamination.

Results: From March 18, 2020 to May 1, 2020, 480 patients were screened by chest CT, and 313 patients had both chest CT and RT-PCR (65%). The cumulative incidence of COVID-19 was 5.4% (95% confidence interval [CI], 3.6-7.8; 26 of 480 patients). Diagnosis of COVID-19 was made before radiation therapy for 22 patients (84.6%) and during RT for 4 patients (15.3%). Chest CT directly aided the diagnosis of 7 cases in which the initial RT-PCR was negative or not feasible, out of a total of 480 patients (1.5%) and 517 chest CT acquisitions. Four patients with COVID-19 at the time of the chest CT screening had a false negative CT. Sensitivity and specificity of chest CT screening in patients with both RT-PCR and chest CT testing were estimated at 0.82 (95% CI, 0.60-0.95) and 0.98 (95% CI, 0.96-0.99), respectively. Adaptation of the radiation therapy treatment was made for all patients, with 7 postponed treatments (median: 5 days; interquartile range, 1.5-14.8).

Conclusions: The benefit of systematic use of chest CT screening during CT simulation for patients undergoing radiation therapy during the COVID-19 pandemic seemed limited.
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http://dx.doi.org/10.1016/j.ijrobp.2021.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887448PMC
July 2021

Radiomics to predict outcomes and abscopal response of patients with cancer treated with immunotherapy combined with radiotherapy using a validated signature of CD8 cells.

J Immunother Cancer 2020 11;8(2)

Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France

Background: Combining radiotherapy (RT) with immuno-oncology (IO) therapy (IORT) may enhance IO-induced antitumor response. Quantitative imaging biomarkers can be used to provide prognosis, predict tumor response in a non-invasive fashion and improve patient selection for IORT. A biologically inspired CD8 T-cells-associated radiomics signature has been developed on previous cohorts. We evaluated here whether this CD8 radiomic signature is associated with lesion response, whether it may help to assess disease spatial heterogeneity for predicting outcomes of patients treated with IORT. We also evaluated differences between irradiated and non-irradiated lesions.

Methods: Clinical data from patients with advanced solid tumors in six independent clinical studies of IORT were investigated. Immunotherapy consisted of 4 different drugs (antiprogrammed death-ligand 1 or anticytotoxic T-lymphocyte-associated protein 4 in monotherapy). Most patients received stereotactic RT to one lesion. Irradiated and non-irradiated lesions were delineated from baseline and the first evaluation CT scans. Radiomic features were extracted from contrast-enhanced CT images and the CD8 radiomics signature was applied. A responding lesion was defined by a decrease in lesion size of at least 30%. Dispersion metrices of the radiomics signature were estimated to evaluate the impact of tumor heterogeneity in patient's response.

Results: A total of 94 patients involving multiple lesions (100 irradiated and 189 non-irradiated lesions) were considered for a statistical interpretation. Lesions with high CD8 radiomics score at baseline were associated with significantly higher tumor response (area under the receiving operating characteristic curve (AUC)=0.63, p=0.0020). Entropy of the radiomics scores distribution on all lesions was shown to be associated with progression-free survival (HR=1.67, p=0.040), out-of-field abscopal response (AUC=0.70, p=0.014) and overall survival (HR=2.08, p=0.023), which remained significant in a multivariate analysis including clinical and biological variables.

Conclusions: These results enhance the predictive value of the biologically inspired CD8 radiomics score and suggests that tumor heterogeneity should be systematically considered in patients treated with IORT. This CD8 radiomics signature may help select patients who are most likely to benefit from IORT.
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http://dx.doi.org/10.1136/jitc-2020-001429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668366PMC
November 2020

Incorporating Magnetic Resonance Imaging (MRI) Based Radiation Therapy Response Prediction into Clinical Practice for Locally Advanced Cervical Cancer Patients.

Semin Radiat Oncol 2020 10;30(4):291-299

Radiation Oncology department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France; Radiation Oncology Department, Oscar Lambret Institute, Lille, France; Faculté de Médecine PARIS Sud, Université Paris Sud, Université Paris Saclay; INSERM1030, Gustave Roussy Cancer Campus, Villejuif France; French Military Health Services Academy, Ecole du Val-de-Grâce, Paris, France; Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France.

In recent years, magnetic resonance imaging (MRI) has become one of the standard imaging tools to define the macroscopic gross tumor volume in locally advanced cervical cancer patients based on T2-weighted sequence. Recent data suggest that functional MRI could be used to potentially improve the delineation of target volumes based on physiologic features, defining radioresistant subvolumes that may require higher doses to achieve local cure. Functional imaging can be used to predict tumor biology and outcome, as well as for assessment of tumor response during radiotherapy. The concept of adaptive radiotherapy relies on the possibility of monitoring variations in target volumes structures to guide treatment-plan modification during radiotherapy, taking into account not only internal movements but also tumor response. With integrated MRI in radiotherapy linear accelerators, motion monitoring during treatment delivery has become available. MRI can be also used to accurately evaluate cervical tumor residual volume after chemoradiotherapy, and therefore allowing a personalized treatment planning for brachytherapy boost, based on tumor radiosensitivity. In this review, we discuss how MRI tumor response assessment could be included into clinical practice during radiation therapy in locally advanced cervical cancer patients.
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http://dx.doi.org/10.1016/j.semradonc.2020.05.007DOI Listing
October 2020

Analysis of Radiation Dose/Volume Effect Relationship for Anorectal Morbidity in Children Treated for Pelvic Malignancies.

Int J Radiat Oncol Biol Phys 2021 01 14;109(1):231-241. Epub 2020 Aug 14.

Department of Radiation Oncology, Gustave Roussy Cancer Campus, Cancer Center, University Paris Saclay Medical Faculty, Villejuif, France; INSERM 1030 Molecular radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France; French Military Health Academy, Ecole du Val-de-Grâce, Paris, France; Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France. Electronic address:

Purpose: To examine dose-volume effect relationships for anorectal morbidity in children treated with image-guided brachytherapy for pelvic tumors.

Methods And Materials: Medical records of all consecutive children with pelvic tumors treated in our center and receiving image-guided pulsed-dose-rate brachytherapy with or without external beam radiation therapy (EBRT) between 2005 and 2019 were reviewed. The effect of the minimal doses to the most exposed 0.5 cm, 1 cm, and 2 cm of the anorectum (respectively: D, D, and D), total reference air kerma (TRAK), and volume of 100% isodose was examined for anorectal toxicities.

Results: Seventy-eight consecutive children were included. Median age was 2.9 years (range, 0.8-14.9 years). Most of the tumors were bladder or prostate (67%) or vaginal (22%) rhabdomyosarcoma. Six patients received EBRT in addition to brachytherapy. Median follow-up was 21.3 months. At last follow-up, 30 children (38%) had experienced Common Terminology Criteria for Adverse Events version 5 grade ≥1 acute or late anorectal events: 24% had grade 1 events, 7.7% had grade 2 events, and 6.4% had grade 3 events. No toxicity greater than grade 3 was observed (eg, fistula or stricture). In univariate analysis, the D and D were significant for probability of grade 1 to 3 (P = .009 and P = .017, respectively) and grade 2 to 3 anorectal morbidity (P = .007 and P = .049, respectively). There was no significant correlation for D (P = .057 for grade 1-3; P = .407 for grade 2-3). A 10% probability (95% confidence interval, 4%-20%) for anorectal toxicity of grade 2 or greater was reached for a D = 52 Gy. The age, EBRT use, TRAK, and treated volume values were not significant.

Conclusions: To our knowledge, this study is the first to show a significant dose-volume effect relationships for anorectal morbidity in children undergoing treatment with brachytherapy. Integrating these data into brachytherapy treatment planning could help to optimize the therapeutic index in these young patients.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.033DOI Listing
January 2021

Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages.

J Immunother Cancer 2020 06;8(1)

INSERM U1030, Molecular Radiotherapy, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

Background: Macrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.

Methods: Since we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.

Results: Using mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages and . The antitumor effect of macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.

Conclusions: Our data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.
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http://dx.doi.org/10.1136/jitc-2020-000622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307581PMC
June 2020

Interaction between the Number of Chemotherapy Cycles and Brachytherapy Dose/Volume Parameters in Locally Advanced Cervical Cancer Patients.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Brachytherapy Unit, Gustave Roussy Cancer Campus, F-94800 Villejuif, France.

Scarce data exist on concurrent chemotherapy in locally advanced cervical cancer (LACC) patients (pts) treated with image-guided adaptive brachytherapy (IGABT). We examined the effect of a number of chemotherapy cycles and their interaction with brachytherapy dose/volume parameters. Clinical records of 209 consecutive pts treated for a LACC were reviewed. Pts received CRT concurrently with cisplatin 40 mg/m² or carboplatin AUC2. An additional cycle could have been delivered during the pulse-dose rate (PDR)-IGABT. The impact of a number of chemotherapy cycles on outcome was examined, as well as the interactions with dose volume parameters. The number of cycles was four in 55 (26.3%) pts, five in 154 (73.7%) including 101 receiving the fifth cycle during IGABT. Median follow-up was 5.5 years. Pts receiving five cycles had a better outcome on all survival endpoints, including three year local control rate (93.9% vs. 77.2%; < 0.05). In the subgroup, only pts with tumor FIGO (Fédération Internationale de Gynécologie Obstétrique) stage ≤IIB or with CTV > 25 cm had a better outcome. Pts receiving four cycles with DCTV > 80Gy had the same locoregional control-(LRC) as those receiving five cycles and achieving DCTV ≤ 80 Gy ( = 0.75). An optimal propensity score matching the balance for the FIGO stage, CTV volume and DCTV confirmed the effect, with the largest life expectancy benefit for locoregional failure-free survival (absolute gain: 1.5 years; = 0.017). Long-term radiation-induced toxicity was not increased. Increasing the total number of cycles from 4 to 5 improved LFS, suggesting a place for systemic strategies aimed at in-field cooperation. Delivering an additional cycle at the time of brachytherapy did not increase morbidity and there permitted an increase in chemotherapy dose intensity.
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http://dx.doi.org/10.3390/jcm9061653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356737PMC
June 2020

Radiobiological optimization comparison between pulse-dose-rate and high-dose-rate brachytherapy in patients with locally advanced cervical cancer.

Brachytherapy 2019 May - Jun;18(3):370-377. Epub 2019 Feb 21.

Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France; INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France; Faculté de médecine PARIS Sud, université Paris Sud, Université Paris Saclay, Paris, France; French Military Health Services Academy, Ecole du Val-de-Grâce, Paris, France; Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France. Electronic address:

Purpose: Only scarce data are available on the possibility to include radiobiological optimization as part of the dosimetric process in cervical cancer treated with brachytherapy (BT). We compared dosimetric outcomes of pulse-dose-rate (PDR) and high-dose-rate (HDR)-BT, according to linear-quadratic model.

Methods And Materials: Three-dimensional dosimetric data of 10 consecutive patients with cervical cancer undergoing intracavitary image-guided adaptive PDR-BT after external beam radiation therapy were examined. A new HDR plan was generated for each patient using the same method as for the PDR plan. The procedure was intended to achieve the same D high-risk clinical target volume with HDR as with PDR planning after conversion into dose equivalent per 2 Gy fractions (EQD2) following linear-quadratic model. Plans were compared for dosimetric variables.

Results: As per study's methodology, the D high-risk clinical target volume was strictly identical between PDR and HDR plans: 91.0 Gy (interquartile: 86.0-94.6 Gy). The median D intermediate-risk clinical target volume was 62.9 Gy with HDR vs. 65.0 Gy with PDR (p < 0.001). The median bladder D was 65.6 Gy with HDR, vs. 62 Gy with PDR (p = 0.004). Doses to the rectum, sigmoid, and small bowel were higher with HDR plans with a median D of 55.6 Gy (vs. 55.1 Gy, p = 0.027), 67.2 Gy (vs. S 64.7 Gy, p = 0.002), and 69.4 Gy (vs. 66.8 Gy, p = 0.014), respectively. For organs at risk (OARs), the effect of radiobiological weighting depended on the dose delivered. When OARs BT contribution to D doses was <20 Gy, both BT modalities were equivalent. OARs EQD2 doses were all higher with HDR when BT contribution to D was ≥20 Gy.

Conclusion: Both BT modalities provided satisfactory target volume coverage with a slightly higher value with the HDR technique for OARs D2 while intermediate-risk clinical target volume received higher dose in the PDR plan. The radiobiological benefit of PDR over HDR was predominant when BT contribution dose to OARs was >20 Gy.
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http://dx.doi.org/10.1016/j.brachy.2018.12.009DOI Listing
December 2019

Total Reference Air Kerma is Associated with Late Bowel Morbidity in Locally Advanced Cervical Cancer Patients Treated with Image-Guided Adaptive Brachytherapy.

J Clin Med 2019 Jan 21;8(1). Epub 2019 Jan 21.

Brachytherapy Unit, Gustave Roussy, 94800 Villejuif, France.

No dose volume parameter has been identified to predict late bowel toxicities in locally advanced cervical cancer (LACC) patients treated with image-guided adaptive brachytherapy. We examined the incidence of bowel toxicities according to the total reference air kerma (TRAK) in 260 LACC patients. In both univariate and multivariate analysis, late morbidity positively correlated with a TRAK ≥2 cGy (centigray) at 1 meter, emphasizing the importance of this parameter in term of late bowel morbidity. There is no validated dose volume parameter to predict late bowel toxicities in cervical cancer patients treated with image-guided adaptive brachytherapy (IGABT). We examined the incidence of bowel toxicities according to the TRAK, which is proportional to the integral dose to the patients. Clinical data of 260 LACC patients treated with curative intent from 2004 to 2016 were examined. Patients received chemoradiation plus a pulse-dose rate IGABT boost. The relationship between TRAK and morbidity was assessed by Kaplan-Meier method, log-rank tests, and Cox proportional-hazards model on event-free periods. Median follow-up was 5.2 years (SE (Standard Error): 0.21). Probability of survival without late bowel toxicity Grade ≥ 2 rate for patients without recurrence ( = 227) at 5 years was 66.4% (SE 3.7). In univariate analysis, bowel and/or sigmoid dose/volume parameters were not significant. Late morbidity positively correlated with active smoking, CTVHR volume >25 cm³, and a TRAK ≥2 cGy at 1 meter. In multivariate analysis, the following factors were significant: Active smoking ( < 0.001; HR: 2.6; 95%CI: 1.4⁻5.0), and the TRAK ( = 0.02; HR: 2.4; 95%CI: 1.2⁻5.0). TRAK was associated with late bowel toxicities probability, suggesting that the integral dose should be considered, even in the era of IGABT.
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http://dx.doi.org/10.3390/jcm8010125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352249PMC
January 2019

Tumor Shrinkage During Chemoradiation in Locally Advanced Cervical Cancer Patients: Prognostic Significance, and Impact for Image-Guided Adaptive Brachytherapy.

Int J Radiat Oncol Biol Phys 2018 10 18;102(2):362-372. Epub 2018 Jun 18.

Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France; INSERM U1030, Gustave Roussy Cancer Campus, Villejuif, France; Department of Surgery, Gustave Roussy, Villejuif, France; French Military Health Services Academy, Ecole du Val-de-Grâce, Paris, France; Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France. Electronic address:

Purpose: To study the prognostic value of gross tumor volume (GTV) shrinkage and its dosimetric implication in a large cohort of patients with cervical cancer receiving definitive chemoradiotherapy plus image guided adaptive brachytherapy.

Methods And Materials: Clinical records of consecutive patients treated in our institution between February 2004 and November 2015 by concurrent chemoradiotherapy (45 Gy in 25 fractions ± lymph node boosts) followed by a magnetic resonance imaging-guided adaptive pulse-dose rate brachytherapy were included. The prognostic value of GTV and its evolution after chemoradiotherapy were examined first on initial staging magnetic resonance imaging and then at time of brachytherapy. All measures and measurement cutoffs were selected using time-dependent area under the curve for 3-year progression-free survival (PFS).

Results: GTV evolution between diagnosis and the time of brachytherapy was assessed in 247 patients. After chemoradiotherapy, complete response was observed in 75 patients (28%). Optimal cutoffs were GTV = 55 cm at diagnosis, GTV = 7.5 cm at brachytherapy, and GTV reduction ≥90%. All patients with volume above or reduction below these cutoffs had significant reduced overall survival, PFS, local control, and distant metastasis control (P < .001). Patients with anemia at diagnosis had a lower tumor volume response rate (P < .001). In multivariate analysis, incorporating the International Federation of Gynecology and Obstetrics stage, N+ stage, anemia, and dosimetric parameters for image guided adaptive brachytherapy, GTV optimal volume reduction after chemoradiotherapy was independently associated with improved overall survival, PFS, local control, and distant metastasis control (P < .001).

Conclusions: These results could provide a rationale for dose de-escalation studies in brachytherapy for patients displaying optimal GTV volumetric reduction after chemoradiotherapy and may reinforce the need for dose escalation in poorly responding patients.
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http://dx.doi.org/10.1016/j.ijrobp.2018.06.014DOI Listing
October 2018

Risk of Late Urinary Complications Following Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: Refining Bladder Dose-Volume Parameters.

Int J Radiat Oncol Biol Phys 2018 06 13;101(2):411-420. Epub 2018 Feb 13.

Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France; Radiotherapy Department, Gustave Roussy, Villejuif, France; Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France; French Military Health Academy, Ecole du Val-de-Grâce, Paris, France. Electronic address:

Purpose: To study correlations between dose-volume parameters of the whole bladder and bladder trigone and late urinary toxicity in locally advanced cervical cancer patients treated with pulsed-dose-rate brachytherapy.

Methods And Materials: Patients with locally advanced cervical cancer treated with chemoradiation therapy and pulsed-dose-rate brachytherapy from 2004 to 2015 were included. Cumulative dose-volume parameters of the whole bladder and bladder trigone were converted into 2-Gy/fraction equivalents (EQD2, with α/β = 3 Gy); these parameters, as well as clinical factors, were analyzed as predictors of toxicity in patients without local relapse.

Results: A total of 297 patients fulfilled the inclusion criteria. The median follow-up period was 4.9 years (95% confidence interval 4.5-5.3 years). In patients without local relapse (n = 251), the Kaplan-Meier estimated grade 2 or higher urinary toxicity rates at 3 years and 5 years were 25.4% and 32.1%, respectively. Minimal dose to the most exposed 2 cm of the whole bladder [Formula: see text] , bladder International Commission on Radiation Units & Measurements (ICRU) (B) dose, and trigone dose-volume parameters correlated with grade 2 or higher toxicity. At 3 years, the cumulative incidence of grade 2 or higher complications was 22.8% (standard error, 2.9%) for bladder [Formula: see text]  < 80 Gy versus 61.8% (standard error, 12.7%) for [Formula: see text]  ≥ 80 Gy (P = .001). In the subgroup of patients with bladder [Formula: see text]  ≤ 80 Gy, a trigone dose delivered to 50% of the volume (D) > 60 Gy was significant for grade 2 or higher toxicity (P = .027). The probability of grade 3 or higher toxicities increased with bladder [Formula: see text]  > 80 Gy (16.7% vs 1.6%; hazard ratio [HR], 5.77; P = .039), B dose > 65 Gy (4.9% vs 1.3%; HR, 6.36; P = .018), and trigone D > 60 Gy (3.1% vs 1.2%; HR, 6.29; P = .028). Pearson correlation coefficients showed a moderate correlation between bladder [Formula: see text] , B dose, and bladder trigone D (P < .0001).

Conclusions: These data suggest that [Formula: see text]  ≤ 80 Gy should be advised for minimizing the risk of severe urinary complications (<15%). Bladder trigone dose was also predictive of severe late urinary toxicity. These constraints need further confirmation in a multicenter prospective setting.
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http://dx.doi.org/10.1016/j.ijrobp.2018.02.004DOI Listing
June 2018
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