Montpellier, France
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Huguet F.,University Paris - Sud | Goodman K.A.,Sloan Kettering Cancer Center | Azria D.,CRLC Val dAurelle Paul Lamarque | Racadot S.,CRLC Leon Berard | Abrams R.A.,Rush University Medical Center
International Journal of Radiation Oncology Biology Physics | Year: 2012

Summary: Pancreatic carcinoma is a leading cause of cancer-related mortality. Approximately 30% of pancreatic cancer patients present with locally advanced, unresectable nonmetastatic disease. For these patients, two therapeutic options exist: systemic chemotherapy or chemoradiotherapy. Within this context, the optimal technique for pancreatic irradiation is not clearly defined. A search to identify relevant studies was undertaken using the Medline database. All Phase III randomized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included, as were some noncontrolled Phase II and retrospective studies. An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines. Each member of the working group independently evaluated five endpoints: total dose, target volume definition, radiotherapy planning technique, dose constraints to organs at risk, and quality assurance. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose intensity concepts. © 2012 Elsevier Inc. All rights reserved.


Azria D.,CRLC Val dAurelle Paul Lamarque | Betz M.,Hopitaux Universitaires Of Geneva Hug | Bourgier C.,Institute Gustave Roussy | Sozzi W.J.,Center Hospitalier Univesitaire Vaudois | Ozsahin M.,Center Hospitalier Univesitaire Vaudois
Critical Reviews in Oncology/Hematology | Year: 2012

The impact of curative radiotherapy depends mainly on the total dose delivered in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many treatments. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced late complications (LC) due to their irreversibility and the potential impact on quality of life. In one population treated with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, low CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of LC. In addition, recent data suggest that patients with severe radiation-induced LC possess 4 or more single nucleotide polymorphisms (SNPs) in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro. On-going studies are being analyzing the entire genome using a genome-wide association study (GWAS). © 2010 Elsevier Ireland Ltd.


Gerard J.-P.,Center Antoine Lacassagne | Chamorey E.,Center Antoine Lacassagne | Gourgou-Bourgade S.,CRLC Val dAurelle Paul Lamarque | Benezery K.,Center Antoine Lacassagne | And 4 more authors.
Radiotherapy and Oncology | Year: 2015

Background: During the ACCORD 12 randomized trial, an evaluation of the clinical tumor response was prospectively performed after neoadjuvant chemoradiotherapy. The correlations between clinical complete response and patient characteristics and treatment outcomes are reported. Material and methods: Between 2005 and 2008 the Accord 12 trial accrued 598 patients with locally advanced rectal cancer and compared two different neoadjuvant chemoradiotherapies (Capox 50: capecitabine + oxaliplatin + 50 Gy vs Cap 45: capecitabine + 45 Gy). An evaluation of the clinical tumor response with rectoscopy and digital rectal examination was planned before surgery. A score to classify tumor response was used adapted from the RECIST definition: complete response: no visible or palpable tumor; partial response, stable and progressive disease. Results: The clinical tumor response was evaluable in 201 patients. Score was: complete response: 8% (16 patients); partial response: 68% (137 patients); stable: 21%; progression: 3%. There was a trend toward more complete response in the Capox 50 group (9.3% vs 6.7% with Cap 45). In the whole cohort of 201 pts complete response was significantly more frequent in T2 tumors (28%; p = 0.025); tumors <4 cm in diameter (14%; p = 0.017), less than half rectal circumference and with a normal CEA level. Clinical complete response observed in 16 patients was associated with more conservative treatment (p = 0.008): 2 patients required an abdomino-perineal resection, 11 an anterior resection and 3 patients benefited from organ preservation (2 local excision, 1 "watch and wait". A complete response was associated with more ypT0 (73%; p < 0.001); ypNO (92%); R0 circumferential margin (100%). Conclusion: These data support the hypothesis that a clinical complete response assessed using rectoscopy and digital rectal examination after neoadjuvant therapy may increase the chance of a sphincter or organ preservation in selected rectal cancers. © 2015 Elsevier Ireland Ltd. All rights reserved.


Jacot W.,CRLC Val dAurelle Paul Lamarque | Lopez-Crapez E.,Laboratoire Of Biologie Specialisee Et Doncogenetique | Thezenas S.,CRLC Val dAurelle Paul Lamarque | Senal R.,Laboratoire Of Biologie Specialisee Et Doncogenetique | And 4 more authors.
Breast Cancer Research | Year: 2011

Introduction: Triple-negative breast cancers (TNBCs) are characterised by lack of expression of hormone receptors and epidermal growth factor receptor 2 (HER-2). As they frequently express epidermal growth factor receptors (EGFRs), anti-EGFR therapies are currently assessed for this breast cancer subtype as an alternative to treatments that target HER-2 or hormone receptors. Recently, EGFR-activating mutations have been reported in TNBC specimens in an East Asian population. Because variations in the frequency of EGFR-activating mutations in East Asians and other patients with lung cancer have been described, we evaluated the EGFR mutational profile in tumour samples from European patients with TNBC.Methods: We selected from a DNA tumour bank 229 DNA samples isolated from frozen, histologically proven and macrodissected invasive TNBC specimens from European patients. PCR and high-resolution melting (HRM) analyses were used to detect mutations in exons 19 and 21 of EGFR. The results were then confirmed by bidirectional sequencing of all samples.Results: HRM analysis allowed the detection of three EGFR exon 21 mutations, but no exon 19 mutations. There was 100% concordance between the HRM and sequencing results. The three patients with EGFR exon 21 abnormal HRM profiles harboured the rare R836R SNP, but no EGFR-activating mutation was identified.Conclusions: This study highlights variations in the prevalence of EGFR mutations in TNBC. These variations have crucial implications for the design of clinical trials involving anti-EGFR treatments in TNBC and for identifying the potential target population. © 2012 Jacot et al.; licensee BioMed Central Ltd.


Leclerc M.,Catholic University of Louvain | Maingon P.,Center Georges Francois Leclerc | Hamoir M.,Catholic University of Louvain | Dalban C.,Center Georges Francois Leclerc | And 4 more authors.
Radiotherapy and Oncology | Year: 2013

Background The simultaneous integrated boost (SIB) technique with dose per fraction slightly higher than 2 Gy offers the advantages of shortening the treatment time and increasing the biologically equivalent dose to the tumor. This study was designed to evaluate the feasibility of a dose-escalating radiotherapy treatment by using a SIB-IMRT approach in patients with early and moderately advanced head and neck cancers. Materials and methods Fifty-seven consecutive patients with pharyngo-laryngeal T2N0 or T2N1, or laryngeal T3N0 SCC were included. The therapeutic PTVs were treated according to three consecutive dose levels i.e., 69 Gy in 30 fractions of 2.3 Gy (dose level I), 72 Gy in 30 fractions of 2.4 Gy (dose level II) or 75 Gy in 30 fractions of 2.5 Gy (dose level III). The prophylactic PTVs received a dose of 55.5 Gy delivered in 30 fractions of 1.85 Gy. The primary endpoint of the study was acute toxicity assessed during treatment and during the first 3 months following the completion of radiotherapy. The secondary endpoints included loco-regional control, disease-free survival, overall survival and late toxicity at 2 years of follow-up. The study design allowed patients to be enrolled in the second dose level group if no more than 10% of grade 4 acute toxicity was observed on the first dose level group within 3 months after the completion of IMRT, and so on for the third level group. Results Forty-four men and 13 women were included in the trial. The majority of them presented with oropharyngeal cancer (53%) and laryngeal cancer (33%). Only 3 patients developed grade 4 acute mucositis during treatment, one in each dose level. Thirty-two patients (56%) experienced grade 3 toxicity, mostly dermatitis and mucositis, without any significant difference between the groups. Late grade 1 and 2 xerostomia was seen in 53% and 33% of patients, respectively. Transient grade 4 late toxicity was observed in 16% of all patients and was equally distributed among the groups. The 2-year loco-regional control was 82% for all 3 groups (79% dose level I, 88% dose level II, 79% dose level III). The 2-year overall survival was 89% for dose level I and II, and 95% for dose level III. Conclusions This dose escalation SIB-IMRT protocol was safe and effective as the sole treatment of early and moderately advanced SCC of head and neck. No toxicity difference was observed between the groups. © 2013 Elsevier Ireland Ltd. All rights reserved.


Vieillot S.,CRLC Val dAurelle Paul Lamarque | Fenoglietto P.,CRLC Val dAurelle Paul Lamarque | Lemanski C.,CRLC Val dAurelle Paul Lamarque | Moscardo C.L.,CRLC Val dAurelle Paul Lamarque | And 4 more authors.
Radiation Oncology | Year: 2012

Purpose: To assess outcomes of patients with carcinoma of the anal canal (CAC) treated with intensity-modulated radiation therapy (IMRT).Method and materials: From August 2007 to January 2011, seventy-two patients suffering from CAC were treated with IMRT. Concurrent chemotherapy was added in case of locally advanced tumors. Radiation course consisted in delivering an initial plan to the PTV1 defined as the primary tumor and the risk area including pelvic and inguinal nodes. Forty-five Gy in daily 1.8 Gy-daily fractions were delivered five days a week. A second plan of 14.4-20 Gy to the primary tumor (PTV2) was administered in 1.8-2 Gy-daily fractions, 5 days a week. We present here the results of dosimetry, toxicities, and clinical outcome of the first 39 patients with a median follow-up of 24 months.Results: Thirty-one women and eight men were included in the present analysis. Tumors were classified as stages I, II, III and IV in 2, 7, 27 and 2 patients, respectively. Median age was 59 years (range, 38-85). Radiotherapy alone (RT) or combined with chemotherapy (RCT) were delivered in 6 (15%) and 33 (85%) patients, respectively.Six patients (15%) required a treatment break ≥ 3 days, and median time for treatment break was 8 days (range, 3-14 days). Acute grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were seen in 10 and 5% of patients, respectively. Grade 4 toxicity was only hematologic and occurred in 12% patients receiving RCT. With a median follow-up of 24 months, no patient experienced any late grade 4 toxicity. The 2-year overall survival rate was 89%, the 2-year local relapse free survival was 77% and the 2-year colostomy-free survival rate was 85%.Conclusion: IMRT is well tolerated with acceptable treatment interruption allowing dose escalation. © 2012 Vieillot et al; licensee BioMed Central Ltd.


Jacot W.,CRLC Val dAurelle Paul Lamarque | Pouderoux S.,CRLC Val dAurelle Paul Lamarque | Thezenas S.,CRLC Val dAurelle Paul Lamarque | Chapelle A.,CRLC Val dAurelle Paul Lamarque | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2012

Patients with locally advanced breast cancer treated with neoadjuvant chemotherapy are at risk of cancer treatment-induced bone loss and consequently of increased skeletal morbidity. In addition, this situation could be worsened by the fact that only a minority of patients with breast cancer have sufficient vitamin D. A comprehensive evaluation of bone homeostasis is critical in this context. We retrospectively evaluated the serum levels of calcium, vitamin D, TRAIL, RANK ligand (RANKL), Osteoprotegerin (OPG), Bone TRAP, CrossLaps and DKK1 in 77 patients (median age:50 years; range 25-74), with locally advanced breast cancer treated in our institute with anthracyclines-taxane neoadjuvant chemotherapy (7 cycles of 21 days/each) between March 2007 and August 2008. Serum samples were collected before the first (baseline) and the last treatment cycle. Variations and correlations between biomarker levels were evaluated. At baseline, 79.5 % of patients had vitamin D insufficiency (<30 ng/ml), increasing to 97.4 % at the end of the neoadjuvant chemotherapy (p<0.0001). Calcium and RANKL serum concentrations were also significantly decreased, while OPG was significantly increased, resulting in lower RANKL/OPG ratio. Calcium and vitamin D, RANKL and vitamin D and RANKL and OPG levels were significantly correlated (Spearman's coefficient r = 0.2721, p = 0.0006; r = 0.1916, p = 0.002; and r = -0.179, p = 0.03, respectively). Nearly all included patients suffered from vitamin D insufficiency by the end of the neoadjuvant chemotherapy with changes in the calcium/RANKL/OPG axis that are evocative of deregulation of a functional regulatory mechanism. Further studies are needed to determine how drugs modulate this regulatory mechanism to preserve bone homeostasis in patients with breast cancer. © Springer Science+Business Media, LLC. 2012.


Llacer-Moscardo C.,CRLC Val DAurelle Paul Lamarque | Quenet F.,CRLC Val DAurelle Paul Lamarque | Azria D.,CRLC Val DAurelle Paul Lamarque | Fenoglietto P.,CRLC Val DAurelle Paul Lamarque
Radiation Oncology | Year: 2010

Background: Radiotherapy for retroperitoneal sarcomas remains controversial and a technical challenge considering the threshold of contiguous critical organs tolerance. We performed consecutive RapidArc dosimetric plans in preoperative or postoperative setting.Methods: A dosimetric study was carried out from six preoperative (group A) and four postoperative (group B) CT-scans, performed in 7 patients.Prescribed dose was 45 and 50 Gy for groups A and B, respectively. The planning target volume (PTV) was defined as the clinical target volume (CTV) plus 5 mm. The CTV encompassed the gross tumor volume (GTV) plus 10 mm or the tumoral bed. The dosimetric plans were optimized on a RapidArc Eclipse console using the progressive resolution algorithm, PRO version 8.8. Normalization method allowed the coverage of 99% of the PTV by 95% of the dose.Results: Mean PTV were 2318.5 ± 2223.9 cc [range 348-6198 cc] and 698.3 ± 216.6 cc [range 463 -933 cc] for groups A and B, respectively. Plans were optimized for single arcs in group B and for single or two arcs in group A. The contralateral kidney volume receiving 5 Gy (V5Gy) was 21.5 ± 23.3% [range 0-55%] and 3.1 ± 2.6% [range 0-7.3%] for groups A and B, respectively. The mean dose received by 1% of the kidney (D1%) was 5.6 ± 2.4 Gy [range 3.6 -7.6 Gy] for group A and 5.4 ± 0.7 Gy [range 4.3-6 Gy] for group B. The volume of small bowel excluding the PTV (small bowel-PTV) that received 40 Gy and 30 Gy (V40Gyand V30Gy) in group A were 7.5 ± 4.4% [range 5.4-14.1%] and 18.5 ± 7.1% [range 10-30.4%], respectively.In group B, small bowel-PTV V40Gyand V30Gywere 4.7 ± 3.3% [range 3.3-8%] and 21.6 ± 7.5% [range 9.4-30%] respectively. In a second step, we treated two patients in the postoperative group. Treatment time delivery with one arc was 74 seconds. No severe acute toxicity was observed.Conclusion: RapidArc technology for retroperitoneal sarcomas showed acceptable dosimetric results in preoperative or postoperative clinical situation. From the first treated patients, acute tolerability was good to excellent. © 2010 Llacer-Moscardo et al; licensee BioMed Central Ltd.


Dubois J.-B.,CRLC Val dAurelle Paul Lamarque | Bussieres E.,French Institute of Health and Medical Research | Richaud P.,French Institute of Health and Medical Research | Rouanet P.,CRLC Val dAurelle Paul Lamarque | And 4 more authors.
Radiotherapy and Oncology | Year: 2011

Purpose: To assess efficacy and tolerance of intra-operative radiation therapy (IORT) in patients suffering from locally advanced rectal cancer, treated with preoperative radiotherapy followed by surgical resection. Methods and materials: In this French, multicenter, comparative, phase III study, 142 patients with locally advanced rectal cancer (T3 or T4 or N+, and M0), treated with a 4-week preoperative radiotherapy (40 grays) were randomly assigned to either surgical resection alone (Control group: n = 69) or combined to 18-gray intra-operative radiation therapy (IORT group: n = 73) between 1993 and 2001. Results: The 5-year cumulative incidence of local control was 91.8% with IORT and 92.8% with surgery alone (p = 0.6018); the mean duration without local relapse (Kaplan-Meier method) was 107 versus 126 months, respectively. No statistically significant difference was demonstrated for overall survival (p = 0.2578) disease-free survival (p = 0.7808) and probability of metastatic relapse (p = 0.6037) with 5-year cumulative incidences of 69.8% versus 74.8%, 63.7% versus 63.1%, and 26.1% versus 30.2%, respectively. 48 patients of the IORT group and 53 patients of the control group were alive with a median follow-up of 60.1 and 61.2 months, respectively. Post-operative complications were observed in the IORT group in 21 patients (29.6%) and in the control group in 13 patients (19.1%) (p = 0.15), with an acceptable tolerance profile. Conclusions: Although this randomized study did not demonstrate any significant improvement in local control and disease-free survival in rectal cancer patients treated with preoperative radiation therapy receiving IORT or not, it confirmed the technical feasibility and the necessity for evaluating IORT for rectal carcinoma in further clinical studies. © 2011 Elsevier Ireland Ltd. All rights reserved.


The several options for therapy in breast cancer underline the difficulties to determine the reliable population which can be treated by a specific adjuvant therapy, and the population in which that therapy could generate morbidity, mortality, "medical surcharge" without prognosis improvement. This problem is particularly accurate in node - negative breast cancer patients. Adjuvant therapy has been proved to be more efficient, so a better definition of the prognosis and the response to adjuvant treatments could allow the selection of a sub-group of patients who can be spared chemotherapy. The quantification of the uPA/PAI-1 tumor content is one of the most relevant prognostic factors in this clinical setting. The integration of the uPA/PAI-1 prognostic information gathered in the multidisciplinary medical consensus meetings could be used to select the node-negative good/prognosis population in which chemotherapy could be avoided. This review will focus on the uPA/PAI-1 system, its biological role and its clinical implications in breast oncology. The different ways to analyse the uPA and PAI-1 content in tumor cells will be also presented and commented. ©John Libbey Eurotext.

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