Publications by authors named "Majed Ben Mrad"

28 Publications

  • Page 1 of 1

Survival after hypofractionation in glioblastoma: a systematic review and meta-analysis.

Radiat Oncol 2020 Jun 8;15(1):145. Epub 2020 Jun 8.

SAINBIOSE U1059, Jean Monnet University, Saint-Etienne, France.

Background: Glioblastoma multiforme (GBM) has a poor prognosis despite a multi modal treatment that includes normofractionated radiotherapy. So, various hypofractionated alternatives to normofractionated RT have been tested to improve such prognosis. There is need of systematic review and meta-analysis to analyse the literature properly and maybe generalised the use of hypofractionation. The aim of this study was first, to perform a meta-analysis of all controlled trials testing the impact of hypofractionation on survival without age restriction and secondly, to analyse data from all non-comparative trials testing the impact of hypofractionation, radiosurgery and hypofractionated stereotactic RT in first line.

Materials/methods: We searched Medline, Embase and Cochrane databases to identify all publications testing the impact of hypofractionation in glioblastoma between 1985 and March 2020. Combined hazard ratio from comparative studies was calculated for overall survival. The impact of study design, age and use of adjuvant temozolomide was explored by stratification. Meta-regressions were performed to determine the impact of prognostic factors.

Results: 2283 publications were identified. Eleven comparative trials were included. No impact on overall survival was evidenced (HR: 1.07, 95%CI: 0.89-1.28) without age restriction. The analysis of non-comparative literature revealed heterogeneous outcomes with limited quality of reporting. Concurrent chemotherapy, completion of surgery, immobilization device, isodose of prescription, and prescribed dose (depending on tumour volume) were poorly described. However, results on survival are encouraging and were correlated with the percentage of resected patients and with patients age but not with median dose.

Conclusions: Because few trials were randomized and because the limited quality of reporting, it is difficult to define the place of hypofactionation in glioblastoma. In first line, hypofractionation resulted in comparable survival outcome with the benefit of a shortened duration. The method used to assess hypofractionation needs to be improved.
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http://dx.doi.org/10.1186/s13014-020-01584-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278121PMC
June 2020

CBCT evaluation of inter- and intra-fraction motions during prostate stereotactic body radiotherapy: a technical note.

Radiat Oncol 2020 Apr 19;15(1):85. Epub 2020 Apr 19.

Department of radiation oncology, Lucien Neuwirth Cancer Institute, 108 Bis, Avenue Albert Raimond, 42270, Saint Priest en Jarez, France.

Background: In most clinical trials, gold fiducial markers are implanted in the prostate to tune the table position before each radiation beam. Yet, it is unclear if a cone-beam computed tomography (CBCT) should be performed before each beam to monitor a possible variation of the organs at risk (OARs) fullness, especially in case of recto-prostatic spacer implantation. The present study aimed at assessing the inter- and intra-fraction movements of prostate, bladder and rectum in patients implanted with a hyaluronic acid spacer and undergoing prostate stereotactic body radiotherapy (SBRT).

Methods: Data about consecutive patients undergoing prostate SBRT were prospectively collected between 2015 and 2019. Inter-and intra-fraction prostate displacements and volume variation of organs at risk (OARs) were assessed with CBCTs.

Results: Eight patients were included. They underwent prostate SBRT (37.5Gy, 5 fractions of 7.5Gy) guided by prostate gold fiducial markers. Inter-fraction variation of the bladder volume was insignificant. Intra-fraction mean increase of the bladder volume was modest (29 cc) but significant (p < 0.001). Both inter- and intra-fraction variations of the rectum volume were insignificant but for one patient. He had no rectal toxicity. The magnitude of table displacement necessary to match the prostate gold fiducial marker frequently exceeded the CTV/PTV margins (0.4 cm) before the first (35%) and the second arc (15%). Inter- and intra-fraction bladder and rectum volume variations did not correlate with prostate displacement.

Conclusion: Major prostate position variations were reported. In-room kV fiducial imaging before each arc seems mandatory. Intra-fraction imaging of the OARs appears unnecessary. We suggest that only one CBCT is needed before the first arc.

Trial Registration: NCT02361515, February 11th, 2015.
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http://dx.doi.org/10.1186/s13014-020-01534-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168857PMC
April 2020

Chemoradiation and granulocyte-colony or granulocyte macrophage-colony stimulating factors (G-CSF or GM-CSF): time to think out of the box?

Br J Radiol 2020 May 4;93(1109):20190147. Epub 2020 Feb 4.

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

Concerns have been raised about potential toxic interactions when colony-stimulating factors (CSFs) and chemoradiation are concurrently performed. In 2006, the ASCO guidelines advised against their concomitant use. Nevertheless, with the development of modern radiotherapy techniques and supportive care, the therapeutic index of combined chemotherapy, radiotherapy, and CSFs is worth reassessing. Recent clinical trials testing chemoradiation in lung cancer let investigators free to decide the use of concomitant CSFs or not. No abnormal infield event was reported after the use of modern radiotherapy techniques and concomitant chemotherapy regimens. These elements call for further investigation to set new recommendations in favour of the association of chemoradiation and CSFs. Moreover, radiotherapy could induce anticancer systemic effects mediated by the immune system and . With combined CSFs, this effect was reinforced in preclinical and clinical trials introducing innovative radioimmunotherapy models. So far, the association of radiation with CSFs has not been combined with immunotherapy. However, it might play a major role in triggering an immune response against cancer cells, leading to abscopal effects. The present article reassesses the therapeutic index of the combination CSFs-chemoradiation through an updated review on its safety and efficacy. It also provides a special focus on radioimmunotherapy.
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http://dx.doi.org/10.1259/bjr.20190147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217575PMC
May 2020

[Radiotherapy and immune suppression: A short review].

Bull Cancer 2020 Jan 19;107(1):84-101. Epub 2019 Dec 19.

Institut de cancérologie Lucien-Neuwirth, département de radiothérapie, 108 bis, avenue Albert-Raimond, BP 60008, 42271 Saint-Priest-en-Jarez cedex, France; Institut de cancérologie Lucien-Neuwirth, département universitaire de recherche et éducation, 108 bis, avenue Albert-Raimond, BP 60008, 42271 Saint-Priest-en-Jarez cedex, France.

The management of patients undergoing immunosuppressive agents is really challenging. Based on precaution principle, it seems mandatory to stop immunosuppressive (or immunomodulating) agents during radiation. Yet, it is impossible in grafted patients. It is possible in patients with autoimmune disease, but in this case, the autoimmune disease might modify patient's radio-sensitivity. We provide a short review about the safety of radiotherapy in grafted/auto-immune patients. The literature is limited with data coming from outdated case-report or case-control studies. It seems that radiotherapy is feasible in grafted patients, but special dose-constraints limitations must probably be considered for the transplant and the other organs at risk. There is very little data about the safety of radiotherapy, when associated with immunomodulating agents. The most studied drug is the methotrexate but only its prescription as a chemotherapy (high doses for a short period of time) was reported. When used as an immunomodulator, it should probably be stopped 4 months before and after radiation. Apart from rheumatoid arthritis, it seems that collagen vascular diseases and especially systemic scleroderma and systemic lupus erythematous feature increased radio-sensitivity with increased severe late toxicities. Transplanted patients and collagen vascular disease patients should be informed that there is very little data about safety of radiation in their case.
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http://dx.doi.org/10.1016/j.bulcan.2019.09.010DOI Listing
January 2020

Chemoradiation phase II trials: re-exploring a world of missed opportunities.

Acta Oncol 2019 Aug 10;58(8):1158-1162. Epub 2019 May 10.

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

Phase II trials are designed to assess the efficacy/toxicity ratio of experimental treatments and select those worth being tested in phase III trials. Although crucial limitations were identified when concurrent chemoradiation (cCRT) phase III trials characteristics were assessed, features of cCRT phase II trials have never been reported. The objective was to describe features of all cCRT phase II trials. Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase II as topic', 'chemoradiotherapy'. Four hundred and fifty-eight cCRT phase II trials were identified. They were mainly multicenter (51.5%), single arm studies (77.7%) published after 2011 (55.0%). The median number of included patients was 52. Primary endpoints were mainly response rate (20.5%), pathological complete response (14.4%) and overall survival (12.6%). The primary endpoint was not defined in 22% of studies. Tumors were mostly lung (23.1%), head and neck (20.3%), colorectal (16.6%) and esophagogastric cancer (14.6%) treated at a locally advanced setting (81.7%). 55.2% of trials used 3D-conformal radiotherapy and 9.1% intensity-modulated radiotherapy, mainly with normo-fractionation (82.0% of the 573 arms with radiotherapy). Radiation technique was not reported in 19.9% of studies. Associated anticancer drugs (563 arms) were mainly conventional chemotherapies (559 arms): cisplatin (46.2%) and 5-fluorouracil (28.3%). Non cytotoxic agents (targeted therapies, immunotherapies) were tested in 97 arms (17%). With a median follow-up of 31 months, acute grades 3-5 were reported in 98.5% of studies and late toxicities in 44.5%. Follow-up was not reported in 17% of studies. cCRT phase II trials featured severe limitations, with outdated radiation techniques, insufficient reporting of crucial data and a small number of included patients. This certainly limited the impact of conclusions and hindered the development of successful phase III trials.
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http://dx.doi.org/10.1080/0284186X.2019.1605194DOI Listing
August 2019

Quality insurance in head and neck cancer multidisciplinary team meetings: A watchful eye on real-life experience.

Oral Oncol 2019 04 26;91:35-38. Epub 2019 Feb 26.

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

Introduction: Although Multidisciplinary Team Management (MDT) is integrated in most international head and neck cancer treatment guidelines, its applications and proceedings were rarely described. The present study explores a 6-year real-life experience in a French Comprehensive Cancer Care Center.

Methods: Patients, tumor and meeting characteristics of all consecutive cases discussed in head and neck MDT meetings between 2010 and 2015 were retrospectively reviewed.

Results: From 2010 to 2015, 1849 cases (accounting for 1786 patients) were discussed in 138 MDT meetings. Median age was 62 (range: 15-96). When reported (n = 310, 16.8%), performance status was ≥2 in 36.1% of patients. Tumors were mainly squamous cell carcinomas (n = 1664, 91.5%) of the larynx/hypo-pharynx (n = 630, 34.4%), oropharynx (n = 518; 28.3%) and oral cavity (n = 339; 18.5%). Tumors were diagnosed at a locally (n = 358, 25%), locally advanced (n = 946, 66%) or metastatic setting (n = 53, 3.7%). Mean number of discussed patients per MDT meeting was 16 (range: 3-32). Most patients were discussed once (n = 1663, 97%). Most patients (n = 969, 52%) underwent treatment before MDT meetings: mainly surgery (n = 709, 73.2%). The mean time between MDT meeting and first radiation course was 21 days (range: 1-116).

Discussion: Optimal multimodal treatment management is based on MDT meetings and results from the interaction and coordination of surgeons, medical and radiation oncologists. In the present series, most patients were discussed once despite the number of expected recurrences, suggesting that the management of tumor progression was not discussed in head and neck MDT meetings. Furthermore, most patients had surgery before MDT meeting, pointing out that MDT role and place still needs to be improved. Finally, the present population significantly differed from patients included in phase III clinical trials, with more advanced age and poorer condition. It calls for the necessity of a high-quality head and neck MDT meeting since evidence-based recommendations should be adapted to patient's frailties.
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http://dx.doi.org/10.1016/j.oraloncology.2019.02.020DOI Listing
April 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

[Innovation in radiotherapy: A glance at 2018].

Bull Cancer 2019 Jan 4;106(1):48-54. Epub 2019 Jan 4.

Institut de cancérologie Lucien Neuwirth, département de radiothérapie, 108 bis, avenue Albert-Raimond, BP60008, 42271 Saint-Priest-en-Jarez cedex, France; Département universitaire de la recherche et de l'enseignement, institut de cancérologie Lucien Neuwirth, 108, bis avenue Albert Raimond, BP60008, 42271 Saint-Priest-en-Jarez cedex, France.

Innovation in radiotherapy should meet multiple challenges, both technically, biologically, clinically and socially. Scientific, technological and biological advances have resulted in major changes in the implementation, indications, and therapeutic index of radiotherapy over the last century. Based on technical innovations (conformal radiotherapy, intensity modulation, CBCT, stereotactic body radiotherapy and MRI embedded system) and knowledge in cancer biology ("oxygen effect", "checkpoints", targeted therapies, molecular profiles and immunotherapy) highlighted in recent decades, the news in radiotherapy is rich and varied. The 2018 news are particularly focused in the role of hypofractionation in prostate cancer, the use of stereotactic body radiotherapy in oligometastatic patients, the possibility of de-intensify treatment in HPV-related oropharynx cancer, and the combination of short-term androgen deprivation to prostate bed salvage radiotherapy. The present manuscript reviews the 2018 latest advances.
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http://dx.doi.org/10.1016/j.bulcan.2018.12.006DOI Listing
January 2019

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

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

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

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

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

[50th anniversary of cisplatin].

Bull Cancer 2017 Feb 15;104(2):167-176. Epub 2016 Dec 15.

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

We have just celebrated the 50th anniversary of cisplatin cytotoxic potential discovery. It is time to take stock… and it seems mainly positive. This drug, that revolutionized the treatment of many cancer types, continues to be the most widely prescribed chemotherapy. Despite significant toxicities, resistance mechanisms associated with treatment failures, and unresolved questions about its mechanism of action, the use of this cytotoxic agent remains unwavering. The interest concerning this "old" invincible drug has not yet abated. Indeed many research axes are in the news. New platinum salts agents are tested, new cisplatin formulations are developed to target tumor cells more efficiently, and new combinations are established to increase the cytotoxic potency of cisplatin or overcome the resistance mechanisms.
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http://dx.doi.org/10.1016/j.bulcan.2016.11.011DOI Listing
February 2017

Targeting stem cells by radiation: From the biological angle to clinical aspects.

World J Stem Cells 2016 Aug;8(8):243-50

Alexis Vallard, Sophie Espenel, Jean-Baptiste Guy, Yaoxiong Xia, Anis El Meddeb Hamrouni, Majed Ben Mrad, Chloé Rancoule, Nicolas Magné, Department of Radiotherapy, Lucien Neuwirth Cancer Institute, 42271 Saint-Priest en Jarez, France.

Radiotherapy is a cornerstone of anticancer treatment. However in spite of technical evolutions, important rates of failure and of toxicity are still reported. Although numerous pre-clinical data have been published, we address the subject of radiotherapy-stem cells interaction from the clinical efficacy and toxicity perspective. On one side, cancer stem cells (CSCs) have been recently evidenced in most of solid tumor primary locations and are thought to drive radio-resistance phenomena. It is particularly suggested in glioblastoma, where CSCs were showed to be housed in the subventricular zone (SVZ). In recent retrospective studies, the radiation dose to SVZ was identified as an independent factor significantly influencing overall survival. On the other side, healthy tissue stem cells radio-destruction has been recently suggested to cause two of the most quality of life-impacting side effects of radiotherapy, namely memory disorders after brain radiotherapy, and xerostomia after head and neck radiotherapy. Recent publications studying the impact of a radiation dose decrease on healthy brain and salivary stem cells niches suggested significantly reduced long term toxicities. Stem cells comprehension should be a high priority for radiation oncologists, as this particular cell population seems able to widely modulate the efficacy/toxicity ratio of radiotherapy in real life patients.
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http://dx.doi.org/10.4252/wjsc.v8.i8.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999651PMC
August 2016

[Prognosis prediction of febrile neutropenia by MASCC score: A retrospective study].

Bull Cancer 2016 Jun 12;103(6):561-70. Epub 2016 May 12.

Hôpital d'instruction des armées du Val-de-Grâce, service d'oncologie et radiothérapie, boulevard du Port-Royal, 75013 Paris, France. Electronic address:

Introduction: The score of the MASCC, by means of clinical criteria, estimates the risk of serious complications in patients with neutropenic fever induced by chemotherapy.

Methods: We retrospectively studied a cohort of patients hospitalized for a neutropenic fever and analyzed complications according to the criteria defined by the MASCC.

Results: Eighty-one neutropenic fevers in 71 patients were identified. Microbiological documentation was obtained in 33% of cases only. Fifty-eight patients (72%) presented with a MASCC score≥21 and were considered as low risk of complications. In the total population, 10 patients died during their hospitalizations for neutropenic fever, 7 in the high-risk group versus 3 in the low risk group, including 2 patients suffering from significant comorbidities not taken into account by MASCC score. Within the low risk group, presence of a metastatic disease and existence of 2 or more comorbidities were associated with a longer duration of hospitalization.

Conclusion: This analysis suggests that the criteria of the MASCC are not always enough to thoroughly identify which patients were at risk of complications or could be treated through outpatient management. By better taking into account the comorbidities and tumoral stage, a better selection of the patients who are likely to receive an ambulatory treatment could be made. To date, hospitalization remains frequently necessary in neutropenic fevers, at least in its initial steps, and the place of the general practitioner remains to be better defined.
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http://dx.doi.org/10.1016/j.bulcan.2016.03.008DOI Listing
June 2016

Safety assessment of molecular targeted therapies in association with radiotherapy in metastatic renal cell carcinoma: a real-life report.

Anticancer Drugs 2016 Jun;27(5):427-32

Departments of aRadiotherapy bMedical Oncology, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez cDepartment of Radiotherapy, General Hospital CH Roanne, Roanne dDepartment of Oncology and Radiotherapy, Val de Grâce Hospital, Paris eDepartment of Medical Oncology, Institut Gustave Roussy, Villejuif fDepartment of Medical Oncology, Léon Bérard Cancer Center, Lyon, France.

Molecular targeted therapies (TT) are the cornerstone of metastatic renal cell carcinoma (RCC) treatment. There is a paucity of data on the safety of the radiotherapy (RT)-TT association in a sequential or a concomitant setting. The aim of the present study is to retrospectively assess the safety of the RT-TT association. From 2006 to 2014, data from 84 consecutive patients treated with RT and TT for metastatic RCC were retrospectively collected. RT-TT sequential and concomitant associations were, respectively, defined by a time interval of more than five TT half-lives and less than or equal to five TT half-lives between the last TT administration and RT initiation. Toxicities in the fields of RT were assessed systematically. As many patients received several TT and RT courses, 136 RT-TT associations were analyzed, with 66 sequential and 70 concomitant schemes. RT was mainly delivered on bone (75%) and brain metastases (14.7%). TT were tyrosine kinase inhibitors (73.5%), mTOR inhibitors (19.8%), and monoclonal antibodies (6.7%). With a median follow-up of 9.5 months, whatever the sequence, no grade≥4 toxicity was reported. Two grade 3 toxicities were reported with sequential (3%) and concomitant (2.9%) RT-TT, respectively. Sequential or concomitant RT-TT associations in metastatic RCC do not seem to cause major toxicity.
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http://dx.doi.org/10.1097/CAD.0000000000000349DOI Listing
June 2016

Thirty years of phase I radiochemotherapy trials: Latest development.

Eur J Cancer 2016 May 23;58:1-7. Epub 2016 Feb 23.

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

Radiochemotherapy is undergoing a complete expansion. Currently, possibilities of treatment combination are skyrocketting, with different anticancer and targeted molecules, different radiotherapy techniques, and dose escalation with each therapy. The development of a modern phase I radiochemotherapy trial becomes more and more complex and should be fully investigated. In the literature, there are no exhaustive reviews describing the necessity of their characteristics. The present article explores historical and current phase I clinical trials involving a combination of radiation therapy and anticancer therapies. Selected trials were identified by searching in PubMed databases. A total of 228 studies were identified in the last three decades, and a portrait of their characteristics is presented. As expected, most frequently studied malignancies were head and neck cancers, followed by non-small cell lung cancer and brain cancer. Toxicity is reported in more than 90% of the studies. Most studies were published since 2010, at the area of targeted therapies, but mainly concerned classical chemotherapies (cisplatin and 5-fluorouracil). The present review highlights some limits. Indeed, methodology seems not optimised and could be based on more accurate methods of dose-escalation. The present portrait of phase I radiochemotherapy trials suggests that radiochemotherapy notion must be reinvented and trials should be adapted to its complexity. Step by step method does not sound like an option anymore. Let us build the future of radiochemotherapy on past evidences.
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http://dx.doi.org/10.1016/j.ejca.2016.01.012DOI Listing
May 2016

Intensity-modulated radiotherapy or volumetric-modulated arc therapy in patients with head and neck cancer: Focus on salivary glands dosimetry.

Head Neck 2016 07 8;38(7):1028-34. Epub 2016 Feb 8.

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

Background: Despite radiotherapy (RT) technical improvements, high salivary dysfunction rates are still reported in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of the present study was to report salivary glands dosimetry with volumetric-modulated arc therapy (VMAT) and intensity-modulated RT (IMRT).

Methods: Dosimetry of consecutive patients receiving IMRT or VMAT for proven HNSCC between 2007 and 2013 were retrospectively reviewed.

Results: Data of 609 patients were studied. Mean dose, mean maximum dose, and mean percentage of salivary gland volume receiving at least 26 Gy (V26) of the contralateral parotid were 24.50 Gy (range, 0-70.4 Gy), 39.08 Gy (range, 0.38-76.45 Gy), and 40.92% (range, 0% to 100%), respectively. Mean and maximum dose on contralateral submandibular gland were 48.18 Gy (range, 0.19-70.73 Gy), and 61.25 Gy (range, 0-75.8 Gy), respectively.

Conclusion: Target volume coverage still has to be prioritized over organs at risk (OAR) sparing with new RT techniques. Submandibular glands are not sufficiently taken into account in guidelines. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1028-1034, 2016.
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http://dx.doi.org/10.1002/hed.24398DOI Listing
July 2016

Intensity-modulated salvage radiotherapy with simultaneous integrated boost for local recurrence of prostate carcinoma: a pilot study on the place of PET-choline for guiding target volume delineation.

Br J Radiol 2016 9;89(1058):20150579. Epub 2015 Dec 9.

1 Department of Radiotherapy, Institut de cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France.

Objective: The aim of this study was to report the first cases of salvage radiotherapy (RT) using the intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) targeted on choline positron emission tomography (PET) uptake in a local recurrent prostate cancer, after a radical prostatectomy.

Methods: Four patients received salvage irradiation for biochemical relapse that occurred after the initial radical prostatectomy. The relapse occurred from 10 months to 6 years with PSA levels ranging from 2.35 to 4.86 ng ml(-1). For each patient, an (18)F-choline PET-CT showed a focal choline uptake in prostatic fossa, with standardized uptake value calculated on the basis of predicted lean body mass (SUL) max of 3.3-6.8. No involved lymph node or distant metastases were diagnosed. IMRT doses were of 62.7 Gy (1.9 Gy/fraction, 33 fractions), with a SIB of 69.3 Gy (2.1 Gy/fraction, 33 fractions) to a PET-guided target volume.

Results: Acute toxicities were limited. We observed no gastrointestinal toxicity ≥grade 2 and only one grade 2 genitourinary toxicity. At 1-month follow-up evaluation, no complication and a decrease in PSA level (6.8-43.8% of the pre-therapeutic level) were reported. After 4 months, a decrease in PSA level was obtained for all the patients, ranging from 30% to 70%. At a median follow-up of 15 months, PSA level was controlled for all the patients, but one of them experienced a distant lymph node recurrence.

Conclusion: Salvage irradiation to the prostate bed with SIB guided by PET-CT is feasible, with biological efficacy and no major acute toxicity.

Advances In Knowledge: IMRT with PET-oriented SIB for salvage treatment of prostate cancer is possible, without major acute toxicity.
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http://dx.doi.org/10.1259/bjr.20150579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985206PMC
May 2016

[Role of general practitioners in cancer screening: A survey in the French armed forces].

Bull Cancer 2015 Dec 25;102(12):993-1001. Epub 2015 Nov 25.

Hôpital d'instruction des armées du Val-de-Grâce, service d'oncologie et de radiothérapie, boulevard du Port-Royal, 75013 Paris, France. Electronic address:

Introduction: The French Military Health Service organizes medical survey of 340,000 military men. The aim of the present study was to evaluate the practices of solid cancer screening of general practitioners in military medical units and to compare the results with the recommendations of the French National Institute of Cancer.

Methods: We conducted a prospective, observational study among general practitioners in Army Medical Unit by sending them a self-assessment questionnaire. Physicians should report on their practices for screening cancers with official screening recommendations. Compliance rates with the recommendations were reviewed. Screening practices for other cancers (prostate cancer, melanoma, thyroid cancer, lung cancer, testicular cancer) were assessed.

Results: A total of 133 questionnaires were analyzed. Despite a strong involvement of army general health practitioners, guidelines adherence rates (examination frequency, ages of screening beginning and ending) were of 4% for cervical cancer, 7% for breast cancer, and 37% for colorectal cancer. Those rates are comparable to those reported with civilian general practitioners. For cancers without screening recommendation, practitioners felt highly concerned, especially for the most common cancers among the military population. One third of physicians stated that they had diagnosed a testicular cancer through routine screening.

Conclusion: Military general health practitioners feel themselves concerned by solid cancer screening, and more particularly for cancers that are the most prevalent in young adults. However, current guidelines are neither known nor applied in routine.
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http://dx.doi.org/10.1016/j.bulcan.2015.10.010DOI Listing
December 2015

Correlation between anthropometric parameters and acute skin toxicity in breast cancer radiotherapy patients: a pilot assessment study.

Br J Radiol 2015 22;88(1055):20150414. Epub 2015 Sep 22.

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

Objective: The objective of the present study was to identify acute skin toxicity risk factors linked to the anthropometric characteristics of patients with breast cancer treated with radiation therapy.

Methods: Consecutive patients with breast cancer were enrolled after breast-conserving surgery and before radiotherapy course. Acute skin toxicity was assessed weekly during the 7 weeks of radiotherapy with the International Classification from National Cancer Institute. Grade 2 defined acute skin toxicity. Patient characteristics and anthropometric measurements were collected.

Results: 54 patients were enrolled in 2013. Eight patients (14.8%) had grade ≥2 toxicity. The average weight and chest size were 65.5 kg and 93.6 cm, respectively. Bra cup size is significantly associated with a risk of grade 2 dermatitis [odds ratio (OR) 3.46, 95% confidence interval (CI) (1.29-11.92), p = 0.02]. Anthropometric breast fat mass measurements, such as thickness of left [OR 2.72, 95% CI (1.08-8.26), p = 0.04] and right [OR 2.45, 95% CI (0.99-7.27), p = 0.05] axillary fat, are correlated with an increased risk. Distance between the pectoral muscle and nipple is a reproducible measurement of breast size and is associated with acute skin toxicity with significant tendency (OR = 2.21, 95% CI (0.97-5.98), p = 0.07).

Conclusion: Breast size and its different anthropometric measurements (thickness of left and right axillary fat, nipple-to-pectoral muscle distance) are correlated with the risk of skin toxicity.

Advances In Knowledge: The present article analyses several characteristics and anthropomorphic measurements of breast in order to assess breast size. A standardized and reproducible protocol to measure breast volume is described.
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http://dx.doi.org/10.1259/bjr.20150414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743460PMC
January 2016

[Screening psychological distress in breast cancer patients on treatment].

Bull Cancer 2015 Oct 19;102(10):845-53. Epub 2015 Sep 19.

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

Objective: The aim of our study was to evaluate emotional distress among women with breast cancer treated by radiotherapy, using a Visual Analogue Scale (an adaptation of the "Distress Thermometer" French version) associated with a Needs Scale with several items, in order to identify patients requiring psychological care.

Method: Our sample is composed of 277 women treated for breast cancer with radiotherapy. Our psychological evaluation is made of a first enquiry using a visual analogue distress scale and complemented by a Needs Scale with several items. A grade above 3 on the visual analogue distress scale is a reliable indicator; a grade above 4 out of 20 leads us to propose the patient a consultation with a psychologist.

Results: Two hundred and sixty-four female patients with a mean age of 61 years are the object of the study. Among them, 59.2% of patients display a disarray of low intensity (psychological suffering graded between 0 and 2) whereas 40% show a grade equal or superior to 3, considered as pathological on a psychological side: 30% of the patients have a grade between 3 et 5 and less than 2% of the patients display a grade reaching 9 or 10. Concerning the Needs Scale, more than 80% of the patients show a total score below 10 out of 20 and we observe a positive correlation between the total score of the Needs Scale with several items and the Visual Analogue Distress Scale score.

Conclusion: Our results highlight the difficulty for most of the patients to cope with emotional distress linked to their disease. We discuss the necessity to increase awareness among caregivers on this psychological distress, through the use of simple tools such as a Visual Analogue Scale associated with a Needs Scale, so as to provide a holistic care for women with breast cancer.
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http://dx.doi.org/10.1016/j.bulcan.2015.07.004DOI Listing
October 2015

What makes real world outcomes in soft tissue sarcomas? A mono-institutional trabectedin experience.

Bull Cancer 2015 Oct 16;102(10):814-22. Epub 2015 Sep 16.

Institut de cancérologie Lucien-Neuwirth, département de radiothérapie, 42270 Saint-Priest-en-Jarez, France. Electronic address:

Introduction: Trabectedin proved its efficacy in relapsed advanced soft tissue sarcomas (STS) in 3 multicenter phase II studies with selected patients. The aim of the present study is to investigate trabectedin efficacy and tolerance in a cohort of "real-life" unselected patients with sarcoma.

Methods: A single-center analysis was carried out on all consecutive patients with histologically proven unresectable advanced or metastatic STS, who received at least one cycle of trabectedin. Data on efficacy and tolerance were retrospectively reported.

Results: From 2004 to 2014, data of 59 patients were reviewed. Median age was 62 years (from 23 to 87). A total of 317 cycles of trabectedin were administered. Twenty-five patients (42%) suffered grade 3-4 hematological toxicity, mainly with neutropenia (22 patients, 37%). Disease control rate was 24%, mainly with stable disease, and 45 patients (76%) experienced disease progression. Median overall survival was 6.6 months (95%CI [4.9-12.6]).

Conclusion: Trabectedin might be an option for patients without any other validated alternative, but phase III study evaluating trabectedin+best supportive care (BSC) versus BSC is necessary.
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http://dx.doi.org/10.1016/j.bulcan.2015.07.010DOI Listing
October 2015

Correlation of Physical Activities and Breast Cancer Characteristics: A Prospective Analysis with Special Focus on Triple Negative Breast Cancer.

Oncology 2015 19;89(5):262-8. Epub 2015 Aug 19.

Dx00E9;partement de Radiothx00E9;rapie, Institut de Cancx00E9;rologie Lucien Neuwirth, Saint-Priest-en-Jarez, France.

Objective: Several studies have demonstrated that daily physical activity (PA) prevents the development of breast cancer. Our objective was to examine the relationship between PA and clinical and biological tumor characteristics in breast cancer patients in order to determine the impact of energy expenditure (EE) on tumor prognosis.

Methods: We pooled data from two prospective studies, including a total of 121 breast cancer patients. The measure of PA was done using the self-completion Population Physical Activity Questionnaire, which was answered by each patient.

Results: Ten patients harbored triple negative (TN) tumors. The mean body mass index (BMI) in the general population and in patients with TN tumors was 24.3 and 25.6, respectively. The mean daily EE (DEE) was 10,266 kJ×24 h(-1) in the general population and 11,212 kJ×24 h(-1) in patients with TN tumors. In the whole population, there was an inverse statistical correlation between BMI and DEE, rest, low PA, and high PA (p=0.0002, p=0.003, p<0001, and p=0.03, respectively). There was a positive correlation between negative estrogen receptor status and intensive PA (p=0.041) and DEE (p=0.007). For TN tumors, there was no significant correlation between BMI and categories of EE.

Conclusions: Lifestyle (weight regulation, PA) should be adapted and personalized according to biological, clinical, and epidemiological characteristics of the tumors.
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http://dx.doi.org/10.1159/000437229DOI Listing
January 2016

Real-World Vinflunine Outcomes in Bladder Cancer in a Single-Institution Study: Moving Beyond Clinical Trials.

Clin Genitourin Cancer 2015 Dec 6;13(6):588-92. Epub 2015 Jun 6.

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

Purpose: Intravenous vinflunine 320 mg/m(2) every 3 weeks plus best supportive care resulted in better overall survival in comparison with best supportive care alone for eligible patients with failure of prior therapy with locally advanced or metastatic transitional cell cancer of urothelial tract (TCCU). The objective of the present study was to describe our real-life experience of vinflunine for treatment of patients with TCCU.

Patients And Methods: We retrospectively investigated all patients with TCCU who received at least 1 cycle of vinflunine.

Results: Nineteen patients were treated between May 2010 and March 2014 in a compassionate-use program. Performance status was poor in our real-life cohort, with 6 patients (32%) with an Eastern Cooperative Oncology Group performance status of 2. Median duration of vinflunine treatment was 2.4 months (range, 0-4.3 months), and median number of cycles was 3 (range, 1-6). Total response rate was 32%, with partial responses only. Disease control rate was 53%, with a median duration of 7.7 months (range, 6.0-9.4 months). Median progression-free survival was 87 days, or 2.9 months (range, 0.7-11.7 months). After vinflunine treatment, 42% of patients received from 1 to 3 additional lines of chemotherapy. The most frequent grade 4 toxicities were constipation (26%), with 3 intestinal obstructions (16%) and 1 mechanical ileus (5%); and asthenia and fatigue (21%).

Conclusion: Vinflunine, as a TCCU second-line chemotherapy, brings benefits, particularly in cases where there is no alternative treatment.
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http://dx.doi.org/10.1016/j.clgc.2015.05.008DOI Listing
December 2015

The evolving locally-advanced non-small cell lung cancer landscape: Building on past evidence and experience.

Crit Rev Oncol Hematol 2015 Nov 7;96(2):319-27. Epub 2015 Jun 7.

Department of Radiotherapy, Institut de cancérologie de la Loire-Lucien Neuwirth, 108 bis, Avenue Albert Raimond, BP 60008, 42271 Saint-Priest en Jarez, France. Electronic address:

Lung cancer is a major public health concern worldwide. Progress in improving 5-year survival is lagging behind comparable survival rates in other common cancers. The majority of patients with locally advanced non-small cell lung cancer (NSCLC) are not suitable for surgical resection, hence the major role of radical radiotherapy. Advances in radiotherapy techniques allow targeted treatment of the disease, whilst minimizing the dose to organs at risk. Recent research into fractionation schedules, with hyperfractionated and accelerated radiotherapy regimens has been promising. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. However, if radical radiotherapy remains the cornerstone of treatment for patients with unresectable advanced NSCLC either as single modality treatment or with concomitant chemotherapy, advances in understanding of tumor molecular biology and targeted drug development should bring targeted agents into the NSCLC management. The development of numerous therapeutic approaches has made the locally advanced NSCLC world change. An up-to-date overview of the current literature on updated chemotherapeutic agents, targeted therapy, immunotherapy, radiotherapy in stage III NSCLC is provided.
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http://dx.doi.org/10.1016/j.critrevonc.2015.05.020DOI Listing
November 2015