Publications by authors named "Sophie Espenel"

48 Publications

SFOG Campus, A new group is born!

J Gynecol Obstet Hum Reprod 2020 Sep 9:101903. Epub 2020 Sep 9.

Institut Bergonie - Bordeaux, France.

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http://dx.doi.org/10.1016/j.jogoh.2020.101903DOI Listing
September 2020

hTERT Protein Expression in Cytoplasm and Nucleus and its Association With HPV Infection in Patients With Cervical Cancer.

Cancer Genomics Proteomics 2020 Sep-Oct;17(5):615-625

Department of Radiation Oncology, Institut de Cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France.

Background: Few studies have analyzed the association between human telomerase reverse transcriptase (hTERT) protein expression (nuclear and cytoplasmic localization), hTERT methylation status, and human papillomavirus (HPV) genotype infection in cervical cancer.

Patients And Methods: One hundred seventy-three patients with cervical cancer were analyzed. hTERT protein expression was detected by immunohistochemistry. hTERT DNA methylation analysis was performed using a PCR-RLB-hTERT assay, targeting two regions of the hTERT promoter. Type specific HPV infection was detected by using GP5+/GP6+PCR-RLB.

Results: hTERT protein expression was found in both cytoplasm and nucleus (78.0% of the samples showed a cytoplasmic localization and 79.8% had a nuclear localization). A statistically significant association was found between alpha 9 and 7 HPV species with a non-methylation pattern of the hTERT promoter and between these species and high expression of hTERT protein with nuclear localization.

Conclusion: hTERT protein is found in both the nucleus and cytoplasm of patients with cervical cancer and confirm the relationship between the non-methylated status of hTERT promoter and some HPV species as well as the relationship between these species and hTERT protein expression.
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http://dx.doi.org/10.21873/cgp.20218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472445PMC
March 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 Jan 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

[HPV: Carcinogenic implications and preventive measures].

Presse Med 2019 Jul - Aug;48(7-8 Pt 1):756-766. Epub 2019 Jul 12.

Institut de cancérologie Lucien-Neuwirth, département de radiothérapie, 108 bis, avenue Albert-Raimond, BP 60008, 42271 Saint-Priest-en-Jarez cedex, France; Laboratoire de radiobiologie cellulaire et moléculaire de Lyon Sud, CNRS UMR 5822, 165, chemin du grand Revoyet, BP 12, 69921 Oullins cedex, France. Electronic address:

Human oncogenic papillomaviruses (HPV) have an increasingly prominent role in the genesis of many cancers. The oncogenic mechanisms associated with HPV are now better known and make it possible to explain the etiopathogenesis of the association. HPV status is now sought for certain cancers and conditions both prognosis and management of patients. Preventive antiviral vaccination has become a real public health issue and aims to effectively reduce the prevalence of cervical, anal and oropharynx cancer, HPV-associated. However, vaccination against HPV still lags behind. The purpose of this review is to redefine the involvement of HPV in several cancers as well as current therapeutic challenges of HPV-related cancers, notably in term of prevention.
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http://dx.doi.org/10.1016/j.lpm.2019.05.019DOI Listing
September 2019

Special Focus on Stage IV Cervical Cancer Patients: A Decade Experience.

Oncology 2019 2;97(3):125-134. Epub 2019 Jul 2.

Department of Radiotherapy, Lucien Neuwirth Cancer Institute, Saint-Priest-en-Jarez, France.

Objectives: The aim of this study was to identify and compare prognostic factors, management strategies, and outcomes of very locally advanced cervical cancer (CC) (i.e., stage IVA) and metastatic CC (i.e., stage IVB).

Method: A retrospective review was conducted based on all consecutive patients treatedfor stage IV CC in a comprehensive cancer care centre between 2004 and 2017.

Results: Sixty-eight patients were included. Performance status (PS) was ≥2 for 35.9%. Median age at diagnosis was 60.5. There were 24 stage IVA CC (35.3%) and 44 stage IVB CC (64.7%). Seventeen patients with stage IVB CC had only para-aortic lymph node metastases (38.6%), 13 had only distant metastases (29.5%), and 14 had both (31.8%). Patients with stage IVA CC experienced a radiotherapy with curative intent (n = 14, 58.3%) +/- concomitant chemotherapy, or a palliative treatment (n = 10, 41.7%). Twenty-three patients with stage IVB CC received a prior chemotherapy (52.3%), 11 a primary concomitant chemoradiation (25%), and 10 a palliative treatment (22.7%). The mean follow-up was 18.0 months. The 5-year overall survival was 5.1% for stage IVA (95% CI = 0.7-33.9), and 10.5% for stage IVB (95% CI = 3.7-29.7). In multivariate analysis, PS >1 was identified as a poor prognostic factor of disease-specific survival for stage IVA CC. PS >1 and pelvic lymph node involvement were identified as poor prognostic factors of overall survival and disease-specific survival for stage IVB CC.

Conclusions: In daily clinical practice, outcomes of stages IV CC are poor. Treatment of advanced and metastatic CC remains challenging. New management strategies are needed, as well as efficient preventive strategies.
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http://dx.doi.org/10.1159/000500025DOI Listing
September 2019

[Brachytherapy: When needs overtake care offer].

Bull Cancer 2019 Jun 10;106(6):584-589. Epub 2019 May 10.

Institut de cancérologie Lucien-Neuwirth, département de radiothérapie, 108 bis, avenue Albert-Raimond, BP 60008, 42271 Saint-Priest-en-Jarez cedex, France. Electronic address:

Brachytherapy has the unique characteristic of being able to deliver high doses to a very localized volume, and remains one of the radiotherapy techniques that has an unparalleled therapeutic index. However, its use has been declining in the past years. Globally, only 55 to 88 % of patients with locally advanced cervical cancer benefit from utero-vaginal brachytherapy, despite the fact that it is proven to enhance both progression-free and overall survival. A decline in the use of low dose rate brachytherapy has likewise been described in the treatment of low-risk and favorable intermediate-risk prostate cancers. Several factors could explain this. First, the radiation oncologists who have the proficiency to perform brachytherapy seems to be inadequate, as it is a technique that requires training and expertise for optimal applications. In many cancer care centers, the caseload is insufficient to provide this experience. Second, the increasing use of technically advanced external beam radiation therapy, such as intensity modulated radiation therapy, offers an easier substitute with more lucrative benefits, resulting in decreased utilization of brachytherapy. However, when brachytherapy is not delivered, a poorer survival rate is reported in locally advanced cervical cancer, and is suggested in intermediate and high-risk prostate cancer. The increasing level of evidence of treatment with brachytherapy necessitates an improvement in its accessibility by having more radiation oncologists as well as cancer centers equipped to perform the procedure.
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http://dx.doi.org/10.1016/j.bulcan.2019.03.017DOI Listing
June 2019

Is breast-conserving therapy adequate in BRCA 1/2 mutation carriers? The radiation oncologist's point of view.

Br J Radiol 2019 May 27;92(1097):20170657. Epub 2019 Feb 27.

3 Department of Radiotherapy, Institut Gustave Roussy , Villejuif , France.

Breast conserving therapy (BCT) is currently a recognized alternative to mastectomy for early BC patients. However, the therapeutic index of BCT was considered controversial for decades in BRCA1/2 mutation carriers. The aim of the present review was to investigate the outcome of mutation carriers undergoing BCT regarding local and distant endpoints. A short review was performed from the point of view of the radiation oncologist. Only retrospective data were available regarding local outcome assessment. They generated conflicting results. In studies with limited follow-up, BCT did not increase the risk of local recurrence in BRCA1/2 mutation carriers non-carriers. Conversely, some studies with longer follow-up supported that local relapse was increased in mutation carriers. Yet, according to some publications, their long-term risk of ipsilateral recurrence post-BCT was not different from general population cohorts. Besides, overall and metastasis-free survivals were the same after BCT regardless of the BRCA1/2 mutation status. Similar survival rates were also reported when BCT and mastectomy were compared in mutation carriers. Regarding acute or late toxicity, normal rates were reported in BRCA mutation carriers after breast radiotherapy. The BRCA1/2 mutation does not seem to widely alter the therapeutic index (efficacy/toxicity ratio) of modern adjuvant breast irradiation. Although the long term equivalence of BCT/mastectomy on local control is still not clearly recognised, BCT can be considered an adequate option for BRCA1/2 mutation carriers. This review highlights that BCT is a reasonable option for BRCA1/2 mutation carriers however litterature is controversial concerning long-term local outcome and results of a large prospective cohort are needed.
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http://dx.doi.org/10.1259/bjr.20170657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580916PMC
May 2019

Safety assessment of anticancer drugs in association with radiotherapy in metastatic malignant melanoma: a real-life report : Radiation/systemic drug combo in metastatic melanoma.

Cancer Chemother Pharmacol 2019 05 26;83(5):881-892. Epub 2019 Feb 26.

Institut de Cancérologie Lucien Neuwirth, 108 bis Avenue Albert Raimond, BP 60008, 42271, St Priest en Jarez cedex, France.

Purpose: To assess the safety of the association of radiotherapy (RT) and systemic treatments for patients with metastatic malignant melanoma (mMM).

Methods: A retrospective analysis included consecutive patients treated with palliative RT, and at least one line of systemic therapy for mMM between 2001 and 2016. Treatments were defined as sequential or concomitant when RT and the systemic drug were administered, respectively, at more or less than five half-lives from each other.

Results: 92 patients were included. They had 110 palliative RT treatments. RT was delivered with a "conventional" chemotherapy (mainly fotemustine and/or dacarbazine) and a "modern" systemic therapy (BRAF inhibitors, association of BRAF and MEK inhibitors, immunotherapy), respectively, in 88 (80%) and 22 (20%) cases. Systemic treatments and RT were mainly concurrently performed (n = 61, 55.5%). Regarding acute grade ≥ 3 toxicity, no difference was reported between sequential and concomitant groups either in the whole cohort (p = 1) or in the subgroup of patients receiving "modern" systemic therapies (p = 1). Acute and late grade ≥ 3 toxicities only occurred with vemurafenib. BRAF inhibitors and RT produced more severe infield adverse events than other associations (p = 0.001) with two deaths.

Conclusion: In our series, compared to sequential administration, concomitant association of systemic anticancer drugs and palliative RT did not increase toxicity in mMM patients. BRAF inhibitors and RT produced severe infield toxicities. Prospective studies are needed to better characterize the toxicity of each association.
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http://dx.doi.org/10.1007/s00280-019-03806-5DOI Listing
May 2019

Radiotherapy in triple-negative breast cancer: Current situation and upcoming strategies.

Crit Rev Oncol Hematol 2018 Nov 12;131:96-101. Epub 2018 Sep 12.

Radiotherapy Department, Lucien Neuwirth Cancer Institute, 42270, St Priest en Jarez, France; Cellular and Molecular Radiobiology Laboratory, CNRS UMR 5822, IPNL, 69622, Villeurbanne, France. Electronic address:

Triple-negative breast cancer (TNBC) (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) is viewed as an aggressive subgroup of breast cancer. Treating patients with TNBC remains clinically challenging. It's now well established than radiation therapy is able to improve locoregional control in breast cancer patients both after breast conserving surgery or mastectomy, with positive impact in high-risk patients for long-term survival. Biologic characterization of breast tumor different subtypes, in particular the heterogeneous subtype of TNBC could permit to adapt the treatment plan. In the present review, summarizing the molecular types, we describe clinical features and postoperative radiotherapy current situation for TNBC, and we provide new strategies and directions through an adapted radiation therapy.
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http://dx.doi.org/10.1016/j.critrevonc.2018.09.004DOI Listing
November 2018

Cancer patients treated with intravenous chemotherapy for the first time. What are their needs? What do they lack? A qualitative-quantitative mixed approach.

Patient Prefer Adherence 2018 19;12:1853-1861. Epub 2018 Sep 19.

Hygee Center, Lucien Neuwirth Cancer Institut, INSERM - CIC-EC, CIC 1408, Saint Priest en Jarez, France,

Introduction: The announcement of cancer coupled with initiation of its treatment impacts patients' psychological and physical states as well as their lifestyles. The objective of this study was to identify and confirm the needs of patients starting off on anticancer chemotherapy treatment.

Methods: This study was based on a qualitative-quantitative mixed method. In 2009, a qualitative study was conducted at the Lucien Neuwirth Cancer Institut for cancer patients undergoing intravenous chemotherapy for the first time. Exploratory and semi-directed interviews were carried out by a sociologist. In 2014, a questionnaire was hetero-administered to 100 patients starting off on chemotherapy.

Results: Forty patients were interviewed in 2009. Ninety-seven patients answered the questionnaire in 2014. Food was a theme that was identified by a majority of patients in 2009 (13/40) and confirmed in 2014: 63% needed help in identifying favorable food and 67% in identifying those that had to be avoided. The other needs identified were those linked to better understanding of the treatment, of how it may affect the couple, its side effects, hygiene and beauty, and knowledge about other treatments. These needs were confirmed in 2014. New needs were elicited in 2014: activities and leisure (33%), psychological needs (32.6%), and family relations (29.9%).

Conclusion: This study enabled us to identify, confirm, and enrich our knowledge of the needs of cancer patients starting off on intravenous chemotherapy. These results led to the modification of an existing patient education program for these patients, in order to fulfill their needs in an updated and tailored manner.
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http://dx.doi.org/10.2147/PPA.S169810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159784PMC
September 2018

Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study.

Clin Genitourin Cancer 2019 Feb 6;17(1):e38-e43. Epub 2018 Sep 6.

Institut Gustave Roussy, Villejuif, France.

Background: About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination.

Patients And Methods: We conducted a multicenter retrospective study among centers from the French Groupe d'Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study.

Results: A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination.

Conclusion: The incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population.
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http://dx.doi.org/10.1016/j.clgc.2018.08.006DOI Listing
February 2019

Outcome and prognostic factors in 593 non-metastatic rectal cancer patients: a mono-institutional survey.

Sci Rep 2018 Jul 16;8(1):10708. Epub 2018 Jul 16.

Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, 108 bis, Avenue Albert Raimond, BP 60008, 42271, Saint-Priest en Jarez, France.

This retrospective study was undertaken to provide more modern data of real-life management of non-metastatic rectal cancer, to compare therapeutic strategies, and to identify prognostic factors of overall survival (OS) in a large cohort of patients. Data on efficacy and on acute/late toxicity were retrospectively collected. Patients were diagnosed a non-metastatic rectal cancer between 2004 and 2015, and were treated at least with radiotherapy. OS was correlated with patient, tumor and treatment characteristics with univariate and multivariate analyses. Data of 593 consecutive non-metastatic rectal cancer patients were analyzed. Median follow-up was 41 months. Median OS was 9 years. Radiotherapy was delivered in pre-operative (n = 477, 80.5%), post-operative (n = 75, 12.6%) or exclusive (n = 41, 6.9%) setting. In the whole set of patients, age, nutritional condition, tumor stage, tumor differentiation, and surgery independently influenced OS. For patients experiencing surgery, OS was influenced by age, tumor differentiation and nodal status. Surgical resection is the cornerstone treatment for locally-advanced rectal cancer. Poor tumor differentiation and node involvement were identified as major predictive factor of poor OS. The research in treatment intensification and in identification of radioresistance biomarkers should therefore probably be focused on this particular subset of patients.
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http://dx.doi.org/10.1038/s41598-018-29040-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048026PMC
July 2018

Outcomes prediction in pre-operative radiotherapy locally advanced rectal cancer: leucocyte assessment as immune biomarker.

Oncotarget 2018 Apr 27;9(32):22368-22382. Epub 2018 Apr 27.

Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint Priest en Jarez, France.

Objective: Leukocytes are hypothesized to reflect the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a large cohort of patients treated with pre-operative radiation for locally advanced rectal cancer (RC).

Results: From 2004 to 2015, 257 RC patients with available biological data underwent a pre-operative radiotherapy, with a median age of 66 years. The median rectal EQD2 was 49.2Gy. Most of patients experienced concurrent chemotherapy ( = 245, 95.4%), mainly with 5-FU (83.3%). Clear surgical margins (i.e. complete resection) were achieved in 234 patients (91.1%). A complete (Mandard TRG1: = 35, 13.6%) or almost complete pathological response (Mandard TRG2: = 56, 21.8%) were achieved in 91 patients (35.4%). With a median follow-up of 46.1 months, 8 patients (3.1%) experienced local relapse, 38 (14.8%) experienced metastases and 45 (17.5%) died. Elevated pre-radiation neutrophil to lymphocyte ratio (NLR > 2.8) was identified as an independent predictive factor of increased local relapse, of decreased progression-free survival and overall survival in multivariate analysis. Elevated NLR was marginally associated with incomplete pathological response in multivariate analysis, suggesting a possible value as a biomarker of radio-sensitivity.

Conclusions: Pre-radiation NLR is a simple and robust biomarker for risk stratification in locally advanced RC patients undergoing pre-operative radiotherapy, and might select the subpopulation eligible to treatment intensification or to neoadjuvant chemotherapy.

Material And Methods: Clinical records from consecutive patients treated in a single institution between 2004 and 2015 with curative-intent radiotherapy were retrospectively analyzed. Classical prognosis factors of RC and peripheral immune markers based on lymphocytes and neutrophil counts were studied.
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http://dx.doi.org/10.18632/oncotarget.25023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976471PMC
April 2018

Biological aspects of chondrosarcoma: Leaps and hurdles.

Crit Rev Oncol Hematol 2018 Jun 22;126:32-36. Epub 2018 Mar 22.

Radiotherapy Department, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France.

Chondrosarcomas are characterized by their chemo- and radioresistance leading to a therapeutic surgical approach which remains the only available treatment with a 10-year survival between 30% and 80% depending on the grade. Non-surgical treatments are under investigation and rely on an accurate biological understanding of drug resistance mechanisms. Novel targeted therapy which represents a new relevant therapeutic approach will open new treatment options by targeting several pathways responsible for processes of proliferation and invasion. Survival pathways such as PI3K, AKT, mTOR and VEGF have been shown to be involved in proliferation of chondrosarcoma cells and antiapoptotic proteins may also play a relevant role. Other proteins such as p53 or COX2 have been identified as potential new targets. This review provides an insight into the biological substantial treatment challenges of CHS and focuses on improving our understanding of CH biology through an overview of major signaling pathways that could represent targets for new therapeutic approaches.
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http://dx.doi.org/10.1016/j.critrevonc.2018.03.009DOI Listing
June 2018

Correction to: From IB2 to IIIB locally advanced cervical cancers: report of a ten-year experience.

Radiat Oncol 2018 03 23;13(1):50. Epub 2018 Mar 23.

Radiotherapy Department, Lucien Neuwirth Cancer Institute, 108 bis avenue Albert Raimond, BP60008, 42271, Saint-Priest-en-Jarez cedex, France.

In the original publication [1] one author name was spelled incorrect.
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http://dx.doi.org/10.1186/s13014-018-0999-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866521PMC
March 2018

Radiotherapy of rectal cancer in elderly patients: Real-world data assessment in a decade.

Dig Liver Dis 2018 Jun 1;50(6):608-616. Epub 2018 Mar 1.

Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France. Electronic address:

Background And Purpose: There is paucity of data on the efficacy and toxicity of radiotherapy in rectal cancer (RC) elderly patients. The objective was to identify management strategies and resulting outcomes in RC patients ≥70 years undergoing radiotherapy.

Material And Methods: A retrospective study included consecutive RC patients ≥70 years undergoing rectal radiotherapy.

Results: From 2004-2015, 340 RC patients underwent pre-operative (n = 238; 70%), post-operative (n = 41, 12%), or exclusive (n = 61, 18%) radiotherapy, with a median age of 78.5 years old (range: 70-96). Radiotherapy protocols were tailored, with 54 different radiotherapy programs (alteration of the total dose, and/or fractionation, and/or volume). Median follow-up was 27.1 months. Acute and late grade 3-4 radio-induced toxicities were reported in 3.5% and 0.9% of patients. Metastatic setting (OR = 6.60, CI95% 1.47-46.03, p = 0.02), exclusive radiotherapy (OR = 5.08, CI95% 1.48-18.21, p = 0.009), and intensity-modulated radiotherapy (OR = 6.42, CI95% 1.31-24.73, p = 0.01) were associated with grade ≥3 acute toxicities in univariate analysis. Exclusive radiotherapy (OR = 9.79, CI95% 2.49-43.18, p = 0.001) and intensity-modulated radiotherapy (OR = 12.62, CI95% 2.05-71.26, p = 0.003) were independent predictive factors of grade ≥3 acute toxicities in multivariate analysis. A complete pathological response was achieved in 12 out of 221 pre-operative patients (5.4%). Age, tumor stage, and surgery were independent predictive factors of survival in multivariate analysis. At end of follow-up, 7.1% of patients experienced local relapse.

Conclusion: Radiotherapy for RC in elderly patients appeared safe and manageable, perhaps due to the tailoring of radiotherapy protocols. Tailored management resulted in acceptable rate of local tumor control.
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http://dx.doi.org/10.1016/j.dld.2018.01.122DOI Listing
June 2018

From IB2 to IIIB locally advanced cervical cancers: report of a ten-year experience.

Radiat Oncol 2018 Feb 2;13(1):16. Epub 2018 Feb 2.

Radiotherapy Department, Lucien Neuwirth Cancer Institute, 108 bis avenue Albert Raimond, BP60008, 42271, Saint-Priest-en-Jarez cedex, France.

Background: Despite screening campaigns, cervical cancers remain among the most prevalent malignancies and carry significant mortality, especially in developing countries. Most studies report outcomes of patients receiving the usual standard of care. It is possible that these selected patients may not correctly represent patients in a real-world setting, which may be a limitation in interpreting outcomes. This study was undertaken to identify prognostic factors, management strategies and outcomes of locally advanced cervical cancers (LACC) treated in daily clinical practice.

Methods: Medical files of all consecutive patients treated with curative intent for LACC in a French Cancer Care Center between 2004 and 2014 were reviewed retrospectively.

Results: Ninety-four patients were identified. Performance status was ≥ 2 in 10.6%. Median age at diagnosis was 63.0. Based on the International Federation of Gynecology and Obstetrics classification, tumours were classified as follows: 10.6% IB2, 22.3% IIA, 51.0% IIB, 4.3% IIIA and 11.7% IIIB. Pelvic lymph nodes were involved in 34.0% of cases. Radiotherapy was delivered for all patients. Radiotherapy technique was intensity modulated radiation therapy or volumetric modulated arc therapy in 39.4% of cases. A concurrent cisplatin chemotherapy was delivered in 68.1% of patients. Brachytherapy was performed in 77.7% of cases. The recommended standard care (concurrent chemoradiotherapy with at least five chemotherapy cycles during radiotherapy, followed by brachytherapy) was delivered in 43.6%. The median overall treatment time was 56 days. Complete tumour sterilisation was achieved in 55.2% of cases. Mean follow-up was 54.3 months. Local recurrence rate was 18.1%. Five-year overall survival was 61.9% (95% Confident Interval (CI) = 52.3-73.2) and five-year disease-specific survival was 68.5% (95% CI = 59.2-79.2). Poor performance status, lymph nodes metastasis and absence of concurrent chemotherapy were identified as poor prognostic factors in multivariate analysis.

Conclusions: Less than 50% of patients received the standard care. Because LACC patients and disease are heterogeneous, treatment tailoring appears to be common in current clinical practice. However, guidelines for tailoring management are not currently available. More data about real-world settings are required in order to to optimise clinical trials' aims and designs, and make them translatable in daily clinical practice.

Trial Registration: retrospectively registered.
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http://dx.doi.org/10.1186/s13014-018-0963-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796580PMC
February 2018

Evaluation of the Cell Invasion and Migration Process: A Comparison of the Video Microscope-based Scratch Wound Assay and the Boyden Chamber Assay.

J Vis Exp 2017 11 17(129). Epub 2017 Nov 17.

UMR CNRS 5822 /IN2P3, IPNL, PRISME, Laboratoire de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon-Sud, Université Lyon 1; Département de Radiothérapie, Institut de Cancérologie de la Loire - Lucien Neuwirth;

The invasion and migration abilities of tumor cells are main contributors to cancer progression and recurrence. Many studies have explored the migration and invasion abilities to understand how cancer cells disseminate, with the aim of developing new treatment strategies. Analysis of the cellular and molecular basis of these abilities has led to the characterization of cell mobility and the physicochemical properties of the cytoskeleton and cellular microenvironment. For many years, the Boyden chamber assay and the scratch wound assay have been the standard techniques to study cell invasion and migration. However, these two techniques have limitations. The Boyden chamber assay is difficult and time consuming, and the scratch wound assay has low reproducibility. Development of modern technologies, especially in microscopy, has increased the reproducibility of the scratch wound assay. Using powerful analysis systems, an "in-incubator" video microscope can be used to provide automatic and real-time analysis of cell migration and invasion. The aim of this paper is to report and compare the two assays used to study cell invasion and migration: the Boyden chamber assay and an optimized in vitro video microscope-based scratch wound assay.
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http://dx.doi.org/10.3791/56337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755419PMC
November 2017

[Impairment of DNA damage response and cancer].

Bull Cancer 2017 Nov 11;104(11):962-970. Epub 2017 Nov 11.

Institut de cancérologie Lucien-Neuwirth, département de radiothérapie, 108 bis, avenue Albert-Raimond, BP60008, 42271 Saint-Priest-en-Jarez cedex, France; Institut de physique nucléaire de Lyon (IPNL), laboratoire de radiobiologie cellulaire et moléculaire, CNRS UMR 5822, 69622 Villeurbanne, France. Electronic address:

Maintaining the genetic integrity is a key process in cell viability and is enabled by a wide network of repair pathways. When this system is defective, it generates genomic instability and results in an accumulation of chromosomal aberrations and mutations that may be responsible for various clinical phenotypes, including susceptibility to develop cancer. Indeed, these defects can promote not only the initiation of cancer, but also allow the tumor cells to rapidly acquire mutations during their evolution. Several genes are involved in these damage repair systems and particular polymorphisms are predictive of the onset of cancer, the best described of them being BRCA. In addition to its impact on carcinogenesis, the DNA damage repair system is now considered as a therapeutic target of choice for cancer treatment, as monotherapy or in combination with other cytotoxic therapies, such as chemotherapies or radiotherapy. PARP inhibitors are nowadays the best known, but other agents are emerging in the field of clinical research. The enthusiasm in this area is coupled with promising results and a successful collaboration between clinicians and biologists would allow to optimize treatment plans in order to take full advantage of the DNA repair system modulation.
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http://dx.doi.org/10.1016/j.bulcan.2017.09.006DOI Listing
November 2017

[Biomarkers of radiation-induced DNA repair processes].

Bull Cancer 2017 Nov 10;104(11):981-987. Epub 2017 Nov 10.

Institut de cancérologie Lucien-Neuwirth, département de radiothérapie, , 108, bis avenue Albert-Raimond, BP60008, 42271 Saint-Priest-en-Jarez cedex, France; Institut de physique nucléaire de Lyon, IPNL, CNRS-UMR-5822, laboratoire de radiobiologie cellulaire et moléculaire, 69622 Villeurbanne, France. Electronic address:

The identification of DNA repair biomarkers is of paramount importance. Indeed, it is the first step in the process of modulating radiosensitivity and radioresistance. Unlike tools of detection and measurement of DNA damage, DNA repair biomarkers highlight the variations of DNA damage responses, depending on the dose and the dose rate. The aim of the present review is to describe the main biomarkers of radiation-induced DNA repair. We will focus on double strand breaks (DSB), because of their major role in radiation-induced cell death. The most important DNA repair biomarkers are DNA damage signaling proteins, with ATM, DNA-PKcs, 53BP1 and γ-H2AX. They can be analyzed either using immunostaining, or using lived cell imaging. However, to date, these techniques are still time and money consuming. The development of "omics" technologies should lead the way to new (and usable in daily routine) DNA repair biomarkers.
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http://dx.doi.org/10.1016/j.bulcan.2017.09.004DOI Listing
November 2017

Healing touch in radiation therapy: is the benefit tangible?

Oncotarget 2017 Oct 30;8(46):81485-81491. Epub 2017 Aug 30.

Département de Radiothérapie, Institut de Cancérologie de la Loire-Lucien Neuwirth, Saint-Priest-en-Jarez, France.

Background: Cancer patients tend to use more and more complementary or alternative medicine concomitantly to radiotherapy. A large part of these patients have recourse to Mind and Body practice, mainly with biofield healers or magnetizers, without any level of evidence. The aim of the present study was to report epidemiologic data on biofield healers in radiation therapy patients, and to assess the possible objective and subjective benefits.

Materials And Methods: A retrospective study was conducted in a French cancer institute. All consecutive breast or prostate cancer patients undergoing a curative radiotherapy during 2015 were screened ( = 806). Healer consultation procedure, frequency, and remuneration were collected. Patient's self-evaluation of healer's impact on treatment tolerance was reported. Tolerance (fatigue, pain) was assessed through visual analogic scale (0 to 10). Analgesic consumption was evaluated. Toxicities were described according to NTCAEv4.0.

Results: 500 patients were included (350 women and 150 men). A total of 256 patients (51.2%) consulted a healer during their radiation treatment, with a majority of women (58%, < 0.01). Most of patients had weekly ( = 209, 41.8%) or daily ( = 84, 16.8%) appointments with their healer. Regarding the self-reported tolerance, > 80% of the patients described a "good" or "very good" impact of the healer on their treatment. Healers were mainly voluntary (75.8%). Regarding the clinical efficacy, no difference was observed in prostate and in breast cancer patients (toxicity, antalgic consumption, pain).

Conclusions: This study reveals that the majority of patients treated by radiotherapy consults a healer and reports a benefit on subjective tolerance, without objective tolerance amelioration.
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http://dx.doi.org/10.18632/oncotarget.20594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655302PMC
October 2017

Dual "mAb" HER family blockade in head and neck cancer human cell lines combined with photon therapy.

Sci Rep 2017 09 22;7(1):12207. Epub 2017 Sep 22.

Université Lyon 1, UMR CNRS 5822 /IN2P3, IPNL, PRISME, Laboratoire de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon-Sud, F-69921, Oullins cedex, France.

Head and neck cancer stem cells (CSCs) are highly resistant to treatment. When EGFR is overexpressed in head and neck squamous cell carcinoma (HNSCC), HER2 and HER3 are also expressed. The aim of the present study was to investigate the effect of HER1/2/3 blockade through a combination of cetuximab and pertuzumab, with or without photon irradiation, on the proliferation and migration/invasion capabilities of an HNSCC chemo- and radioresistant human cell line (SQ20B) and its corresponding stem cell subpopulation. Cell proliferation, migration and invasion were studied after treatment with cetuximab +/- pertuzumab +/- 10 Gy photon irradiation. EGFR, phospho-EGFR, HER2 and HER3 protein expression levels were studied. Activation or inhibition of the RAS/MAPK and AKT-mTOR downstream signalling cascades was investigated through phospho-AKT and phospho-MEK1/2 expression. Cetuximab strongly inhibited SQ20B and FaDu cell proliferation, migration and invasion, whereas it had little effect on SQ20B-CSCs. Cetuximab-pertuzumab combined with radiation significantly inhibited SQ20B and FaDu cell and SQ20B-CSC proliferation, migration and invasion. Cetuximab-pertuzumab with 10 Gy photon irradiation switched off both phospho-AKT and phospho-MEK1/2 expression in the three populations. The triple therapy is therefore thought to inhibit SQ20B cells, SQ20B-CSCs and FaDu cells through an AKT-mTOR and Ras-MAPK downstream signalling blockade.
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http://dx.doi.org/10.1038/s41598-017-12367-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610257PMC
September 2017

Brain metastases from non-small cell lung carcinoma: Changing concepts for improving patients' outcome.

Crit Rev Oncol Hematol 2017 Aug 20;116:32-37. Epub 2017 May 20.

Department of Radiotherapy, Lucien Neuwirth Cancer Institute, 108 bis, Avenue Albert Raimond, BP 60008, 42271 Saint-Priest en Jarez, France; Laboratoire de Radiobiologie Cellulaire et Moléculaire, CNRS UMR 5822, Institut de Physique Nucléaire de Lyon, IPNL, 69622 Villeurbanne, France. Electronic address:

The management of Non Small Cell Lung Cancer (NSCLC) brain metastases is challenging, as this frequent complication negatively impacts patients' quality of life, and can be a life-threatening event. Through a review of the literature, we discuss the main therapeutic options and the recent developments that improved (and complicated) the management of NSCLC brain metastases patients. Most current validated approaches are local with exclusive or combined surgery, whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRT). At the same time, there is a growing role for systemic treatments that might significantly postpone WBRT. Targeted therapies efficacy/toxicity profile remains to be defined but predictive and prognostic molecular factors integration could help to select treatments fully adapted to life expectancy and progression risk.
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http://dx.doi.org/10.1016/j.critrevonc.2017.05.007DOI Listing
August 2017

In Vitro Cell Death Determination for Drug Discovery: A Landscape Review of Real Issues.

J Cell Death 2017 24;10:1179670717691251. Epub 2017 Feb 24.

Département de Radiothérapie, Institut de Cancérologie de la Loire Lucien Neuwirth, Saint-Priest-en-Jarez, France.

Cell death plays a crucial role for a myriad of physiological processes, and several human diseases such as cancer are characterized by its deregulation. There are many methods available for both quantifying and qualifying the accurate process of cell death which occurs. Choosing the right assay tool is essential to generate meaningful data, provide sufficient information for clinical applications, and understand cell death processes. In vitro cell death assays are important steps in the search for new therapies against cancer as the ultimate goal remains the elaboration of drugs that interfere with specific cell death mechanisms. However, choosing a cell viability or cytotoxicity assay among the many available options is a daunting task. Indeed, cell death can be approached by several viewpoints and require a more holistic approach. This review provides an overview of cell death assays usually used in vitro for assessing cell death so as to elaborate new potential chemotherapeutics and discusses considerations for using each assay.
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http://dx.doi.org/10.1177/1179670717691251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392044PMC
February 2017

The world of targeted therapies in kidney cancers: pitfalls, tips and tricks.

Onco Targets Ther 2017 3;10:1375-1380. Epub 2017 Mar 3.

Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France.

In the past few years, metastatic renal cell carcinoma prognosis was improved by the development of molecular targeted therapies (TTs). At the metastatic stage, the tolerance to treatment is a major concern, not only because of the challenge of the efficacy/toxicity ratio improvement but also because of the importance of an optimal adherence to oral treatments. The present case series relates the issues of dealing with uncommon and sometimes never described side effects of sunitinib and sorafenib. The first case report deals with grade 3 vomiting during hemodialysis with concurrent administration of sunitinib. The second case is an iterative gout attack induced by sunitinib. The third case presents a grade 3 scalp dysesthesia with sorafenib. The fourth case includes an astonishing efficacy of metronomic (ie, low doses during a long period of time) bevacizumab in monotherapy. Multidisciplinary management and systematic reporting of unexpected efficacies and toxicities are needed to better understand TTs real therapeutic index. Although TTs revolutionized metastatic renal cell cancer prognosis, they also brought about previously unknown side effects. Identification and management of these off-target effects may be tricky, and therefore, comedication must be wisely chosen. As the physiopathology of these side effects is still unclear, multidisciplinary management and systematic reporting of toxicities are essential.
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http://dx.doi.org/10.2147/OTT.S127919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344426PMC
March 2017

Lysophosphatidic acid (LPA) as a pro-fibrotic and pro-oncogenic factor: a pivotal target to improve the radiotherapy therapeutic index.

Oncotarget 2017 Jun;8(26):43543-43554

Radiotherapy Department, Lucien Neuwirth Cancer Institute, Saint-Priest-en-Jarez, France.

Radiation-induced fibrosis is widely considered as a common but forsaken phenomenon that can lead to clinical sequela and possibly vital impairments. Lysophosphatidic acid is a bioactive lipid involved in fibrosis and probably in radiation-induced fibrosis as suggested in recent studies. Lysophosphatidic acid is also a well-described pro-oncogenic factor, involved in carcinogenesis processes (proliferation, survival, angiogenesis, invasion, migration). The present review highlights and summarizes the links between lysophosphatidic acid and radiation-induced fibrosis, lysophosphatidic acid and radioresistance, and proposes lysophosphatidic acid as a potential central actor of the radiotherapy therapeutic index. Besides, we hypothesize that following radiotherapy, the newly formed tumour micro-environment, with increased extracellular matrix and increased lysophosphatidic acid levels, is a favourable ground to metastasis development. Lysophosphatidic acid could therefore be an exciting therapeutic target, minimizing radio-toxicities and radio-resistance effects.
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http://dx.doi.org/10.18632/oncotarget.16672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522168PMC
June 2017

Preclinical models in HNSCC: A comprehensive review.

Oral Oncol 2017 02 28;65:51-56. Epub 2016 Dec 28.

Université Lyon 1, Faculté de Médecine-Lyon-Sud, 69921 Oullins, France; Laboratoire de Radiobiologie Cellulaire et Moléculaire, CNRS UMR 5822, Institut de Physique Nucléaire de Lyon, IPNL, 69622 Villeurbanne, France; Département de Radiothérapie, Institut de Cancérologie de la Loire - Lucien Neuwirth, 42270 St Priest en Jarez, France. Electronic address:

Head and neck cancer remains a significant public health concern. About 60% of patients die within 5years due to local recurrence. Head and neck squamous cell carcinoma (HNSCC) cell lines are important preclinical models in the search for new therapies against this disease. Furthermore, there is a need to test novel drugs before introduction into clinical practice. A preclinical model that closely resembles the in vivo situation would be highly valuable. In the last few decades, a multicellular spheroid model has gained attention as its behavior was comparable to in vivo tumors. Basic research is necessary to achieve an understanding of the normal and pathological state but cannot, in itself, provide sufficient information for clinical applications. Indeed, animal models are an inevitable prelude to assess the efficacy of new therapeutic approaches in HNSCC. The present review proposes an overview of HNSCC pre-clinical models in order to further understand the oncogenic properties for HNSCC and translate these findings into clinic for patients.
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http://dx.doi.org/10.1016/j.oraloncology.2016.12.010DOI Listing
February 2017

Melanoma: Last call for radiotherapy.

Crit Rev Oncol Hematol 2017 Feb 10;110:13-19. Epub 2016 Dec 10.

Department of Radiotherapy, Lucien Neuwirth Cancer Institute, 108 bis avenue Albert Raimond, BP60008, 42271 Saint Priest en Jarez cedex, France; Department of Medical Oncology, Lucien Neuwirth Cancer Institute, 108 bis avenue Albert Raimond, BP60008, 42271 Saint Priest en Jarez cedex, France. Electronic address:

Melanoma is traditionally considered to be a radioresistant tumor. However, radiotherapy and immunotherapy latest developments might upset this radiobiological dogma. Stereotactic radiotherapy allows high dose per fraction delivery, with high dose rate. More DNA lethal damages, less sublethal damages reparation, endothelial cell apoptosis, and finally clonogenic cell dysfunction are produced, resulting in improved local control. Radiotherapy can also enhance immune responses, inducing neoantigens formation, tumor antigen presentation, and cytokines release. A synergic effect of radiotherapy with immunotherapy is expected, and might lead to abscopal effects. If hadrontherapy biological properties seem able to suppress hypoxia-induced radioresistance and increase biological efficacy, ballistic advantages over photon radiations might also improve radiotherapy outcomes on usually poor prognosis locations. The present review addresses biological and clinical effects of high fraction dose, bystander effect, abscopal effect, and hadrontherapy features in melanoma. Clinical trials results are warranted to establish indications of innovative radiotherapy in melanoma.
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http://dx.doi.org/10.1016/j.critrevonc.2016.12.003DOI Listing
February 2017

Immunotherapy in head and neck cancer: Harnessing profit on a system disruption.

Oral Oncol 2016 11 9;62:153-162. Epub 2016 Sep 9.

Radiotherapy Department, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France; Radiobiology Laboratory, Lyon Medicine University, Lyon, France. Electronic address:

Immune system deregulation and evasion play a key role in cancers' evolution and progression, including squamous cell carcinoma of the head and neck (SCCHN). Development of basic research proposed a whole new vision of cancer treatment, based on a strong biological rational, and targeting intrinsic deregulations. Immunotherapies provide an encouraging strategy for patients' improved outcomes. Immune-based therapies could act on cancer growth and/or development throughout many pathways. If cetuximab is for now the only monoclonal antibody approved for SCCHN management, other strategies, e.g. immune checkpoints openers, are arousing enthusiasm. Clinical trials are multiplying in patients with recurrent/metastatic SCCHN and primary results offer promising outcomes. Prospects of combining various immunotherapies with more established treatments, such as chemotherapy and radiotherapy, seem very encouraging and could provide synergistic benefits. Ongoing phase III clinical trials should soon enlighten us on the next "standard of care" for SCCHN. In the present review we summarized the different immunotherapy strategies that are currently under clinical investigation for SCCHN' medical care.
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http://dx.doi.org/10.1016/j.oraloncology.2016.09.002DOI Listing
November 2016