Publications by authors named "Pierre Meeus"

67 Publications

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer.

J Immunother Cancer 2021 Feb;9(2)

Sorbonne Université; Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, Paris, France.

Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of , a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.
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http://dx.doi.org/10.1136/jitc-2020-001903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883858PMC
February 2021

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

Lancet Oncol 2021 02 18;22(2):256-266. Epub 2021 Jan 18.

Department of Digestive Surgery, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Background: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone.

Methods: We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m) or open (460 mg/m) abdomen techniques, and systemic chemotherapy (400 mg/m fluorouracil and 20 mg/m folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed.

Findings: Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035).

Interpretation: Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases.

Funding: Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.
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http://dx.doi.org/10.1016/S1470-2045(20)30599-4DOI Listing
February 2021

Molecular Characterization of Ovarian Yolk Sac Tumor (OYST).

Cancers (Basel) 2021 Jan 9;13(2). Epub 2021 Jan 9.

Centre Léon Berard (CLB), 69008 Lyon, France.

Most patients with malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and chemotherapy provides curative treatment; however, patients with yolk sac tumors (OYSTs) have a significantly worse prognosis. OYSTs are rare tumors and promising results are expected with the use of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens. We initiated a project in collaboration with EORTC SPECTA, to explore the molecular characteristics of OYSTs. The pilot project used retrospective samples from ten OYST relapsed and disease-free patients. Each patient had a molecular analysis performed with FoundationOne CDx describing the following variables according to the Foundation Medicine Incorporation (FMI): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (for patient's tumor type and other tumor types), tumor mutational burden (TMB), and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 had a molecular analysis. A molecular alteration was identified in four patients (40%). A subset of three patients (33.3% of all patients) harbored targetable oncogenic mutations in , , . Two patients at relapse harbored a targetable mutation. This retrospective study identifies clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate the efficacy of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens and to explore the potential relationship of a molecular alteration and patient outcome.
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http://dx.doi.org/10.3390/cancers13020220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826864PMC
January 2021

Outcomes of patients with metastatic gastrointestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib as first-line treatment.

ESMO Open 2020 11;5(6):e001082

Sarcoma Group, Gustave Roussy, Villejuif, France.

Background: Imatinib is the standard first-line therapy in metastatic gastrointestinal stromal tumours (GIST). Investigational multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result either in increased survival or in early emergence of resistance to approved MKIs.

Methods: To assess whether using MKIs other than imatinib in first line decreases imatinib efficacy in second line for patients with GIST, a retrospective chart review was performed from 2005 to 2011 in two French tertiary centres of patients with GIST who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by imatinib as second line.

Results: Of 46 patients, (55% women, median age 55 years (range 24-81)), 22 (47%) had a exon 11 mutation, 1 a exon 9 mutation (2%), 1 a mutation (2%). Out of 46 patients, 21 (46%) received masitinib, 17 (37%) received dasatinib and 8 (17%) received nilotinib as first-line treatment with a median progression-free survival of 18.0 months (95% CI: 8.5 to 25.5). Median time to imatinib failure was 19.7 months (95% CI: 13.5 to 29.0). Median time to second relapse was 48.7 months (95% CI: 31.2 to 72.0). Median overall survival from time of initial metastasis diagnosis was 5.7 years (95% CI: 4.5 to 7.4).

Conclusions: Patients with GIST who received investigational MKIs as first-line treatment and imatinib as second line had a time to second relapse longer than that observed historically with imatinib in first line, suggesting that using MKIs other than imatinib in first line does not decrease the efficacy of subsequent treatment lines.
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http://dx.doi.org/10.1136/esmoopen-2020-001082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703411PMC
November 2020

Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2020 10 14;21(10):1366-1377. Epub 2020 Sep 14.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival.

Methods: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018.

Findings: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events.

Interpretation: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma.

Funding: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
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http://dx.doi.org/10.1016/S1470-2045(20)30446-0DOI Listing
October 2020

Molecular Classification of Endometrial Stromal Sarcomas Using RNA Sequencing Defines Nosological and Prognostic Subgroups with Different Natural History.

Cancers (Basel) 2020 Sep 11;12(9). Epub 2020 Sep 11.

Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.

A series of 42 patient tumors diagnosed as endometrial stromal sarcoma (ESS) based on the morphology but negative for and/or rearrangement in FISH was analyzed by RNA-sequencing. A chromosomal rearrangement was identified in 31 (74%) of the cases and a missense mutation in known oncogenes/tumor suppressor genes in 11 (26%). Cluster analyses on the expression profiles from this series together with a control cohort composed of five samples of low grade ESS harboring a fusion, one high grade ESS harboring a -ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series of -rearranged family of tumor ( = 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed of -rearranged samples that contained seven ESS samples, one mainly composed of -fused ESS ( = 15) and the last composed of various molecular subtypes ( = 19). These three subgroups display different gene signatures, different in silico cell cycle scores and very different clinical presentations, natural history and survival (log-rank test, = 0.004). While fusion genes may be present in both high and low grade ESS, the high-grade presents with additional or gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.
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http://dx.doi.org/10.3390/cancers12092604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563240PMC
September 2020

Impact of multidisciplinary tumour board in the management of ovarian carcinoma in the first-line setting. Exhaustive analysis from the Rhone-Alpes region.

Eur J Cancer Care (Engl) 2020 Nov 7;29(6):e13313. Epub 2020 Sep 7.

Oncology Department, Leon Berard Cancer Center, Lyon, France.

Objective: Epithelial ovarian cancer (EOC) is a poor prognosis disease partly linked to diagnosis at an advanced stage. The quality of care management is a factor that needs to be explored, more specifically optimal organisation of first-line treatment.

Methods: A retrospective study, dealing with all patients diagnosed within the Rhone-Alpes region with initial diagnosis EOC in 2012, was performed. The aim was to describe the impact of multidisciplinary tumour boards (MTB) in the organisation of care and the consequence on the patient's outcomes.

Results: 271 EOC were analysed. 206 patients had an advanced EOC. Median progression-free survival (PFS) is 17.8 months (CI95%, 14.6-21.2) for AOC. 157 patients (57.9%) had a front-line surgery versus 114 patients (42.1%) interval debulking surgery. PFS for AOC patients with no residual disease is 24.3 months compared with 15.3 months for patients with residual disease (p = .01). No macroscopic residual disease is more frequent in the patients discussed before surgery in MTB compared with patients not submitted before surgery (73% vs. 56.2%, p < .001).

Conclusion: These results highlight the heterogeneity of medical practices in terms of front-line surgery versus interval surgery, in the administration of neoadjuvant chemotherapy and in the setting of MTB discussion.
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http://dx.doi.org/10.1111/ecc.13313DOI Listing
November 2020

Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study.

Lancet Oncol 2020 09 24;21(9):1147-1154. Epub 2020 Jul 24.

Department of Surgical Oncology, University Hospital Gustave Roussy, Villejuif, France.

Background: Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases.

Methods: We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m, or oxaliplatin 300 mg/m plus irinotecan 200 mg/m, plus intravenous fluorouracil 400 mg/m), or mitomycin-HIPEC (mitomycin 35 mg/m) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394.

Findings: Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0-54·8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61-1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients.

Interpretation: Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes.

Funding: French National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30322-3DOI Listing
September 2020

Detailed overview on rare malignant ovarian tumors.

Bull Cancer 2020 Mar 27;107(3):385-390. Epub 2020 Feb 27.

Department of Medical Oncology, centre Léon-Bérard, University Claude Bernard (UCBL Lyon1), Lyon, France. Electronic address:

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.
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http://dx.doi.org/10.1016/j.bulcan.2020.01.011DOI Listing
March 2020

Comparison of postoperative complications and quality of life between patients undergoing continent versus non-continent urinary diversion after pelvic exenteration for gynecologic malignancies.

Int J Gynecol Cancer 2020 02 2;30(2):233-240. Epub 2019 Dec 2.

Institut Claudius Regaud, Toulouse, Occitanie, France

Background: Pelvic exenteration and its reconstructive techniques have been associated with high postoperative morbidity and a negative impact on patient quality of life. The aim of our study was to compare postoperative complications and quality of life in patients undergoing continent compared with non-continent urinary diversion after pelvic exenteration for gynecologic malignancies.

Methods: We designed a multicenter study of patients from 10 centers who underwent an anterior or total pelvic exenteration with urinary reconstruction for histologically confirmed persistent or recurrent gynecologic malignancy after previous treatment with radiotherapy. From January 2005 to September 2008, we included patients retrospectively, and from September 2008 to May 2009, patients were included prospectively which allowed collection of quality of life data. Demographic, surgical, and follow-up data were analyzed. Postoperative complications were classified according to the Clavien-Dindo classification. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 (V.3.0) and EORTC-QLQ-OV28 quality of life questionnaires. We compared patients who underwent a continent urinary diversion with those who underwent a non-continent reconstruction.

Results: We included 148 patients, 92 retrospectively and 56 prospectively. Among them, 77.4% had recurrent disease and 22.6% persistent disease after the primary treatment. In 70 patients, a urinary continent diversion was performed, and 78 patients underwent a non-continent diversion. Median age of the continent and incontinent groups was 53.5 (range 33-78) years and 57 (26-79) years, respectively. There were no significant differences between the continent and non-continent groups in median length of hospitalization (28.5 vs 26 days, P=0.19), postoperative grade III-IV complications (42.9% vs 42.3%, P=0.95), complications needing surgical (27.9% vs 34.6%, P=0.39) or radiological (14.7% vs 12.8%, P=0.74) intervention, and complication type (digestive (23.2% vs 16.7%, P=0.32) and urinary (15.9% vs 16.7%, P=0.91)). There were no significant differences between the groups in global health, global quality of life, and body image perception scores 1 year after surgery.

Conclusion: Continent and incontinent urinary reconstructions are equivalent in terms of postoperative complications and quality of life scores.
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http://dx.doi.org/10.1136/ijgc-2019-000863DOI Listing
February 2020

Watch and Wait Approach for Re-excision After Unplanned Yet Macroscopically Complete Excision of Extremity and Superficial Truncal Soft Tissue Sarcoma is Safe and Does Not Affect Metastatic Risk or Amputation Rate.

Ann Surg Oncol 2019 Oct 23;26(11):3526-3534. Epub 2019 Jul 23.

Department of Medical Oncology and Surgery, Gustave Roussy Institute, Villejuif, France.

Background: The benefits of systematic re-excision (RE) after initial unplanned excision (UE) of soft tissue sarcoma (STS) are unknown.

Objective: The aim of this study was to evaluate the impact of delayed RE versus systematic RE after UE on overall survival (OS), metastatic relapse-free survival (MRFS), local relapse-free survival (LRFS), and rate of amputation.

Methods: Patients who underwent complete UE, without metastasis or residual disease, for primary extremity or superficial STS between 2007 and 2013 were analyzed. The amputation rate, LRFS, MRFS, and OS were assessed in cases of systematic RE in sarcoma referral centers (Group A), systematic RE outside of community centers (Group B), or without RE (Group C).

Results: Groups A, B, and C included 300 (48.2%), 71 (11.4%), and 251 (40.4%) patients, respectively. Median follow-up was 61 months and 5-year OS was 88.4%, 87.3%, and 88% in Groups A, B, and C, respectively (p = 0.22), while 5-year MFRS was 85.4%, 86.2%, and 84.9%, respectively (p = 0.938); RE (p = 0.55) did not influence MRFS. The 5-year LRFS was 83%, 73.5%, and 63.8% in Groups A, B and C, respectively (p = 0.00001). Of the 123 local recurrences observed, 0/28, 1/15, and 5/80 patients in Groups A, B, and C, respectively, required amputation (p = 0.41). Factors influencing LRFS were adjuvant radiotherapy [hazard ratio (HR) 0.21; p = 0.0001], initial R0 resection (HR 0.24, p = 0.0001), and Group A (HR 0.44; p = 0.01).

Conclusion: Systematic RE in sarcoma centers offers best local control but does not impact OS. Delayed RE at the time of local relapse, if any, could be an option.
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http://dx.doi.org/10.1245/s10434-019-07494-6DOI Listing
October 2019

Adjuvant therapy with imatinib in gastrointestinal stromal tumors (GISTs)-review and perspectives.

Transl Gastroenterol Hepatol 2019 9;4:24. Epub 2019 Apr 9.

Department of Medical Oncology, Centre Leon Berard, Lyon, France.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract. Most of them (>75%) are driven by an oncogenic initiating event involving activating mutations of the genes encoding for tyrosine kinase, KIT or platelet derived growth factor receptor alpha (PDGFRA). Efficacy of the tyrosine kinase Inhibitor imatinib is now well established for advanced disease. For localized GISTs, 3 years treatment is the recommended adjuvant therapy for high risk patients. Whether a longer duration and selection of patients for this adjuvant therapy in localized GISTs remains is not yet established (PERSIST-5 study). Similarly, it will be important to further refine the definition of the population of GIST patients at high risk of relapse including molecular criteria (, ESMO guidelines 2018). This review aims to describe current knowledges on the issue of adjuvant therapy of primary GISTs in view of available results.
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http://dx.doi.org/10.21037/tgh.2019.03.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509420PMC
April 2019

Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis.

J Clin Oncol 2019 08 14;37(23):2028-2040. Epub 2019 May 14.

1Centre Hospitalier Universitaire (CHU) Lyon Sud, Lyon, France.

Purpose: Gastric cancer (GC) with peritoneal metastases (PMs) is a poor prognostic evolution. Cytoreductive surgery (CRS) yields promising results, but the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial. Here we aimed to compare outcomes between CRS-HIPEC versus CRS alone (CRSa) among patients with PMs from GC.

Patients And Methods: From prospective databases, we identified 277 patients with PMs from GC who were treated with complete CRS with curative intent (no residual nodules > 2.5 mm) at 19 French centers from 1989 to 2014. Of these patients, 180 underwent CRS-HIPEC and 97 CRSa. Tumor burden was assessed using the peritoneal cancer index. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of HIPEC and account for confounding factors.

Results: After IPTW adjustment, the groups were similar, except that median peritoneal cancer index remained higher in the CRS-HIPEC group (6 2; = .003). CRS-HIPEC improved overall survival (OS) in both crude and IPTW models. Upon IPTW analysis, in CRS-HIPEC and CRSa groups, median OS was 18.8 versus 12.1 months, 3- and 5-year OS rates were 26.21% and 19.87% versus 10.82% and 6.43% (adjusted hazard ratio, 0.60; 95% CI, 0.42 to 0.86; = .005), and 3- and 5-year recurrence-free survival rates were 20.40% and 17.05% versus 5.87% and 3.76% ( = .001), respectively; the groups did not differ regarding 90-day mortality (7.4% 10.1%, respectively; = .820) or major complication rate (53.7% 55.3%, respectively; = .496).

Conclusion: Compared with CRSa, CRS-HIPEC improved OS and recurrence-free survival, without additional morbidity or mortality. When complete CRS is possible, CRS-HIPEC may be considered a valuable therapy for strictly selected patients with limited PMs from GC.
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http://dx.doi.org/10.1200/JCO.18.01688DOI Listing
August 2019

Outcome of Patients with Soft-Tissue Sarcomas: An Age-Specific Conditional Survival Analysis.

Oncologist 2019 07 23;24(7):e559-e564. Epub 2019 Apr 23.

Department of Medicine, Institut Bergonié, Bordeaux, France

Background: Soft-tissue sarcomas (STSs) are a group of rare cancers that can occur at any age. Prognostic outcomes of patients with STS are usually established at the time of the patient's initial disease presentation. Conditional survival affords a dynamic prediction of prognosis for patients surviving a given period after diagnosis. Estimates of conditional survival can provide crucial prognostic information for patients and caregivers, guide subsequent cancer follow-up schedules, and impact decisions regarding management. This study aims to estimate conditional survival and prognostic factors in patients with STS according to age at diagnosis (≤75 years and ≥75 years).

Subjects, Materials, And Methods: A total of 6,043 patients with nonmetastatic STS at first diagnosis who underwent complete surgical resection (R0 or R1) were assessed. Cox proportional hazards regression was used to establish prognostic factors of conditional metastasis-free survival and overall survival at 1, 2, and 5 years after diagnosis.

Results: Elderly patients have more adverse prognostic features at presentation and tend to receive less aggressive treatment than do younger patients. However, at baseline as well as at each conditional survival time point, the 5-year estimated probability of metastatic relapse decreases in both young and elderly patients and is almost identical in both groups at 2 years and 5 years after initial diagnosis. Prognostic factors for metastatic relapse and death change as patient survival time increases in both young and elderly patients. Grade, the strongest prognostic factor for metastatic relapse and death at baseline, is no longer predictive of metastatic relapse in patients surviving 5 years after initial diagnosis. Leiomyosarcoma is the histological subtype associated with the highest risk of metastatic relapse and death in young patients surviving 5 years after initial diagnosis. The positive impact on the outcome of peri-operative treatments tends to decrease and disappears in patients surviving 5 years after initial diagnosis.

Conclusion: Conditional survival estimates show clinically relevant variations according to time since first diagnosis in both young and elderly patients with STS. These results can help STS survivors adjust their view of the future and STS care providers plan patient follow-up.

Implications For Practice: For patients with sarcoma who are followed up years after being treated for their disease, a common scenario is for the patient and caregivers to ask practitioners what the longer-term prognosis may be. The question posed to practitioners may be, "Doc, am I now cured? It's been 5 years since we finished treatment." Survival probability changes for patients who survive a given period of time after diagnosis, and their prognosis is more accurately described using conditional survival. By analyzing more than 6,000 sarcoma patients, an overall improvement was found in the risk of relapse as patients conditionally survive. Prognostic factors for metastatic relapse and death change as patient survival time increases in both young and elderly patients.
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http://dx.doi.org/10.1634/theoncologist.2018-0641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656454PMC
July 2019

Sarcomas in patients over 90: Natural history and treatment-A nationwide study over 6 years.

Int J Cancer 2019 10 15;145(8):2135-2143. Epub 2019 Apr 15.

Centre Léon Bérard, University Claude Bernard Lyon I, Lyon, France.

Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc.org French national database. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor board (MDTB), funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB, second pathological review, and collection of sarcoma patient characteristics and follow-up are collected in a database Information of patients registered from January 1, 2010, to December 31, 2016, in NETSARC were collected, analyzed and compared to the younger population. Patients with sarcomas aged >90 have almost exclusively sarcomas with complex genomics (92.0% vs. 66.3%), are less frequently metastatic (5.3% vs. 14·7%) at diagnosis, have more often superficial tumors (39.8% vs. 14.7%), as well as limbs and head and neck sites (75.2% vs. 38.7%) (all p < 0.001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (p < 0.001). These patients were less frequently operated in NETSARC centers, as compared to those of younger age groups including aged 80-90. However, local relapse-free survival, metastatic relapse-free survival and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0.001). Patients over 90 who were not operated had worse overall survival than younger patients (9.9 vs. 27.3 months, p < 0.001). Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse-free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.
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http://dx.doi.org/10.1002/ijc.32307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767526PMC
October 2019

Very long-term survivors among patients with metastatic soft tissue sarcoma.

Cancer Med 2019 04 27;8(4):1368-1378. Epub 2019 Mar 27.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

Background: Metastatic soft tissue sarcomas (STS) are a group of rare and heterogeneous mesenchymal tumors with a poor prognosis. The aim of this study was to evaluate the incidence of long-term survivors and describe their presentation and management in a large cohort of patients with metastatic STS.

Methods: We collected information of patients with metastatic STS managed in Centre Leon Berard between 1985 and 2015 aiming to compare the group of patients alive 5 years after the diagnosis of metastases vs the others. Prognostic factors of patients and tumors characteristics were investigated by logistic regression analysis. For "long-term survivors," we explored therapeutic strategies at metastatic stage.

Results: Out of 436 patients enrolled, 39 (9%) were still alive 5 years after diagnostic of metastases with a median survival of 146 months (12 years). This "long-term survivors" group included more female and younger patients, with better performance status, more synovial sarcoma or endometrial stromal sarcoma, more patients with simple genomic sarcomas, lower tumor grade, smaller tumor, and longer disease-free interval. In multivariate analysis, age below 55 at metastatic stage (P = 0.0002) and grade 1 tumor (P < 0.0001) were significantly associated with the "long-term survivors." Their therapeutic management was usually aggressive (intensified or polychemotherapy, repeated local treatment of metastases), leading to 62% of complete response in first-line setting.

Conclusions: Very long-term survivors are observed in metastatic STS. Selection of patients in good condition with less aggressive tumor and administration of intensive treatment may lead to obtain these motivating results in a poor prognosis disease.
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http://dx.doi.org/10.1002/cam4.1931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488206PMC
April 2019

Distal extremities soft tissue sarcomas: Are they so different from other limb localizations?

J Surg Oncol 2019 Mar 4;119(4):479-488. Epub 2019 Jan 4.

Faculté de Médecine de la Timone, Génétique Médicale et génomique fonctionnelle, UMR S910 Inserm, Université Aix-Marseille 2, Marseille, France.

Background And Objectives: Soft tissue sarcoma localization in distal extremities (DESTS) of the limbs (hand/fingers, and foot/toes) is unusual. The literature is scarce about their behavior and this study was designed to assess their epidemiological characteristics, outcomes, and prognosis compared to other limb localizations (OLSTS).

Methods: From 1980 to 2010, adult DESTS and OLSTS in 22 centers were included. Demographics, tumor type, treatment modalities, and latest follow-up status were collected. Primary endpoints were overall survival and local/metastatic recurrence incidences.

Results: Two hundred five DESTS and 3001 OLSTS were included. The patients were younger, with more female and smaller tumors in DESTS. There were more clear cell/epithelioid sarcomas, synovial sarcomas, and myxoid liposarcomas vs more dedifferentiated liposarcomas in OLSTS. DESTS tumors were less irradiated and more often amputated (24.3% vs 3.4%). The five-year survival rate was 78.2% compared to 68.6% in OLSTS and after multivariate analysis, STS localization did not impact survival or local/metastatic recurrence.

Conclusion: Though rare and smaller than other limb localizations, DESTS are to be considered as aggressive. Despite a higher amputation rate, the prognosis remains the same as in OLSTS. Limb sparing vs amputation should be carefully assessed in DESTS, especially if grade 3 or of a poor prognosis histological subtype.
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http://dx.doi.org/10.1002/jso.25359DOI Listing
March 2019

Localized Myxofibrosarcomas: Roles of Surgical Margins and Adjuvant Radiation Therapy.

Int J Radiat Oncol Biol Phys 2018 10 2;102(2):399-406. Epub 2018 Jun 2.

Department of Surgery, Curie Institute, Paris, France.

Purpose: The objective of this study was to describe the outcome and prognostic factors for adults treated for localized myxofibrosarcoma.

Methods And Materials: We conducted a retrospective multicenter study of 425 nonmetastatic patients who underwent surgery between January 1996 and December 2015 in French National Group and were enrolled in the Conticabase. Pathologic diagnosis was systematically reviewed by expert pathologists. The endpoints were relapse-free and metastasis-free survival. Log-rank tests and Cox models have been used to identified prognostic factors.

Results: Median age was 66 years; 53% were males; 85% of cases occurred in limbs or superficial trunk; median size was 60 mm; 47% and 39% were grades 2 and 3, respectively; 66% had R0 resection and 34% R1 resection. Adjuvant radiation therapy was given to 65% of patients, neoadjuvant radiation therapy to 3%, neoadjuvant chemotherapy to 7%, and adjuvant chemotherapy to 13%. The median follow-up was 51 months. The 5-year local relapse-free survival was 67%; independent prognostic factors for local relapse were R1 resection (hazard ratio [HR] = 1.26; P = .001) and adjuvant radiation therapy (HR = 0.35; P = .0001) (ie, R1 resection and no adjuvant radiation therapy increase the hazard ratio). In stratified analysis, adjuvant radiation therapy was beneficial after R0 resection (P = .0020) and after R1 resection (P = .0001). The 5-year overall survival was 80%. The 5-year metastasis-free survival was 83%. Independent prognostic factors for metastatic relapse were grade 3 disease (HR = 1.975; P = .0001) and tumor size (HR = 1.006; P = .001).

Conclusions: This large series of myxofibrosarcoma confirms the high rate of local relapse. Combination of R0 resection and adjuvant radiation therapy provided the best local control. In parallel with an increasing rate of R0 resection and adjuvant radiation therapy, we observed a constant improvement in both metastatic and local relapse-free survival during the study.
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http://dx.doi.org/10.1016/j.ijrobp.2018.05.055DOI Listing
October 2018

A comparison of Australian and French families affected by sarcoma: perceptions of genetics and incidental findings.

Per Med 2018 01;15(1):13-24

The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.

Aim: To compare Australian and French perceptions of genetics and preferences regarding the return of incidental findings.

Methods: Participants from the International Sarcoma Kindred Study received a survey at intake to cancer referral units. A total of 1442 Australian and 479 French individuals affected by sarcoma and their unaffected family members responded to four hypothetical scenarios depicting hereditary conditions of varying treatability and severity.

Results: Australians' preference for the return of incidental findings was consistently higher than French for all scenarios. Country group differences were significant for two scenarios when individual characteristics were controlled through multivariable analyses.

Conclusion: Findings support the need for guidelines that are sensitive to sociocultural context and promote autonomous decision-making.
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http://dx.doi.org/10.2217/pme-2017-0035DOI Listing
January 2018

The cost-saving effect of centralized histological reviews with soft tissue and visceral sarcomas, GIST, and desmoid tumors: The experiences of the pathologists of the French Sarcoma Group.

PLoS One 2018 5;13(4):e0193330. Epub 2018 Apr 5.

Department of Anatomopathology, Institut Bergonié, Bordeaux, France.

Objective: This study examined the types of discordance occurring in the diagnosis of soft tissue and visceral sarcomas, gastrointestinal stromal tumors (GIST), and desmoid tumors, as well as the economic impact of diagnostic discrepancies.

Methods: We carried out a retrospective, multicenter analysis using prospectively implemented databases performed on a cohort of patients within the French RRePS network in 2010. Diagnoses were deemed to be discordant based on the 2013 World Health Organization (WHO) classification. Predictive factors of discordant diagnoses were explored. A decision tree was used to assess the expected costs of two strategies of disease management: one based on revised diagnoses after centralized histological review (option 1), the other on diagnoses without centralized review (option 2). Both were defined based on the patient and the disease characteristics, according to national or international guidelines. The time horizon was 12 months and the perspective of the French National Health Insurance (NHI) was retained. Costs were expressed in Euros for 2013. Sensitivity analyses were performed using low and high scenarios that included ± 20% estimates for cost.

Results: A total of 2,425 patients were included. Three hundred forty-one patients (14%) had received discordant diagnoses. These discordances were determined to mainly be benign tumors diagnosed as sarcomas (n = 124), or non-sarcoma malignant tumors diagnosed as sarcomas (n = 77). The probability of discordance was higher for a final diagnosis of desmoid tumors when compared to liposarcomas (odds ratio = 5.1; 95%CI [2.6-10.4]). The expected costs per patient for the base-case analysis (low- and high-case scenarios) amounted to €8,791 (€7,033 and €10,549, respectively) for option 1 and €8,904 (€7,057 and €10,750, respectively) for option 2.

Conclusions: Our findings highlight misdiagnoses of sarcomas, which were found to most often be confused with benign tumors. Centralized histological reviews are likely to provide cost-savings for the French NHI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193330PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886412PMC
July 2018

Being treated in higher volume hospitals leads to longer progression-free survival for epithelial ovarian carcinoma patients in the Rhone-Alpes region of France.

BMC Health Serv Res 2018 01 4;18(1). Epub 2018 Jan 4.

Univ Lyon, Léon Bérard Cancer Center, EA 7425 HESPER, F-69008, Lyon, France.

Background: To investigate the relationship between hospital volume activities and the survival for Epithelial Ovarian Carcinoma (EOC) patients in France.

Methods: This retrospective study using prospectively implemented databases was conducted on an exhaustive cohort of 267 patients undergoing first-line therapy during 2012 in the Rhone-Alpes Region of France. We compared Progression-Free Survival for Epithelial Ovarian Carcinoma patients receiving first-line therapy in high- (i.e. ≥ 12 cases/year) vs. low-volume hospitals. To control for selection bias, multivariate analysis and propensity scores were used. An adjusted Kaplan-Meier estimator and a univariate Cox model weighted by the propensity score were applied.

Results: Patients treated in the low-volume hospitals had a probability of relapse (including death) that was almost two times (i.e. 1.94) higher than for patients treated in the high-volume hospitals (p < 0.001).

Conclusion: To our knowledge, this is the first study conducted in this setting in France. As reported in other countries, there was a significant positive association between greater volume of hospital care for EOC and patient survival. Other factors may also be important such as the quality of the surgical resection.
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http://dx.doi.org/10.1186/s12913-017-2802-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755403PMC
January 2018

A Retrospective Multicentric Study of Ewing Sarcoma Family of Tumors in Patients Older Than 50: Management and Outcome.

Sci Rep 2017 12 20;7(1):17917. Epub 2017 Dec 20.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

Ewing's sarcoma family of tumors (EFTs) is a group of rare and aggressive tumors. Data on EFTs in patients (pts) ≥ 50 years are limited and these pts are often not eligible for clinical trials. Some, but not all, studies have reported inferior outcome for older pts with EFTs. We conducted an IRB-approved retrospective analysis among centers of the French Sarcoma Group on pts diagnosed with EFTs at age ≥50 between 2000 and 2012. Clinical features, treatment modality and outcomes were analyzed. Seventy-seven pts were identified, including 36 females (46.8%) and the median age at diagnosis was 56 years (range: 50-86). The primary tumor was located in soft tissue in 59 pts (76.6%). Fifty-six pts (72.7%) had localized disease, among them 49 (87.5%) received chemotherapy in addition to local therapy. Their estimated 3-yr OS and event-free survival (EFS) rates were respectively 73.3% and 62.2%. Recurrence occurred in 43 pts. The estimated 3-yr OS rate was 37% in pts with metastatic disease at presentation. EFTs in pts ≥50 years are more likely to originate from soft tissue and their outcomes appear to be worse than that of younger pts treated with modern protocols.
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http://dx.doi.org/10.1038/s41598-017-17733-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738347PMC
December 2017

Location of Mutation in Gene and Survival in Patients with Ovarian Cancer.

Clin Cancer Res 2018 01 30;24(2):326-333. Epub 2017 Oct 30.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of gene affects the clinical outcome of ovarian cancer patients. A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for and genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer ( = 316) was used as a validation cohort. In the study cohort, 78 patients were carriers of germline mutations of After adjustment for FIGO stage and macroscopic residual disease, carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20-0.64; = 0.001] and prolonged PFI (29.7 vs. 15.5 months, = 0.011), compared with noncarriers. carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; = 0.094) or PFI (19 vs. 15.5 months, = 0.146). In the TCGA cohort, only carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; = 0.001). Among ovarian cancer patients, carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2136DOI Listing
January 2018

Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma.

Br J Cancer 2017 Dec 12;117(12):1787-1797. Epub 2017 Oct 12.

Department of Translational Research & UMR1052, CRCL, Centre Léon Bérard, 28 Rue Laennec, Lyon 69008, France.

Background: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS.

Methods: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro.

Results: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS.

Conclusions: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.
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http://dx.doi.org/10.1038/bjc.2017.354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729471PMC
December 2017

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BMC Med 2017 Apr 10;15(1):78. Epub 2017 Apr 10.

Department of Medicine, Institut Bergonié, Bordeaux, France.

Background: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals.

Methods: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed.

Results: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis.

Conclusions: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.
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http://dx.doi.org/10.1186/s12916-017-0831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385590PMC
April 2017

Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort).

PLoS One 2017 3;12(2):e0158406. Epub 2017 Feb 3.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

Purpose: The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma.

Experimental Design: Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort.

Results: The median age was 61 years (range 16-92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers.

Conclusions: This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158406PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291382PMC
August 2017

Identification of intra-hepatic communicating veins through the arch sign on CT-scan.

Surg Radiol Anat 2017 Jun 25;39(6):673-677. Epub 2016 Oct 25.

Department of Surgical Oncology, Centre Léon Bérard, 28 Rue Laennec, 69008, Lyon, France.

Purpose: Knowledge of vascular outflow is essential in liver surgery. Communicating veins between the right hepatic vein (RHV) and the middle hepatic vein (MHV) have been described and allowed us to perform new surgical procedures. The aim of this study was to predict the existence of intra-hepatic venous anastomosis by identifying communicating veins on 2D CT-scan imaging.

Methods: We retrospectively analysed data from 32 patients operated on for liver tumours between 2004 and 2013 who underwent a bisegmentectomy VI-VII enlarged to the RHV and/or a bisegmentectomy VII-VIII and/or a left hepatectomy enlarged to the MHV and who had pre and post-operative CT-scans. Patients with cirrhosis were excluded. We first analysed post-operative images and, in patients with a proven collateral vein, looked for evidence of this on pre-operative imaging. We then validated this pre-operative sign against post-operative imaging.

Results: Collaterals from both the RHV and the MHV formed an arch visible on pre-operative imaging which predicted the development of intrahepatic venous anastomosis in 20 patients. In 14 patients, a perfect match between the arch sign and development of collaterals was observed (n = 28). Sensitivity, specificity, negative and positive predictive values were 87, 80, 80, and 87%, respectively. Positive and negative likelihood ratio tests were 4.3 and 0.16, respectively.

Conclusion: Communicating veins between the RHV and the MHV are frequent and can be predicted by the arch sign on 2D CT-scan. Hence the arch sign can be very useful when planning liver surgery.
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http://dx.doi.org/10.1007/s00276-016-1762-2DOI Listing
June 2017

Portal supply of segment IV of the liver based on CT-scan.

Surg Radiol Anat 2017 May 18;39(5):471-476. Epub 2016 Oct 18.

Department of Surgical Oncology, Léon Bérard Cancer Centre, 28 Rue Laennec, 69008, Lyon, France.

Background: The portal vascularization of segment IV (S4) of the liver has not been well described. Knowledge of the portal supply to S4 is of great interest for liver surgery and for interventional radiological procedures. This study aimed to analyse the distribution of portal vein branches supplying S4.

Methods: We retrospectively analysed data from patients operated on for liver tumours between 2007 and 2016. Patients with involvement of S4 branches or the left portal vein, previous liver surgery or poor quality imaging were excluded. Branches originating from the right portal vein and/or from the transverse part of the left portal vein (TPLPV) and/or from the umbilical part of the portal vein (UPLPV) were identified.

Results: In 102 patients who underwent a right hepatectomy, S4 was vascularized by 2-8 branches of the left portal vein, with 84.3 % of patients having 3-6 branches. Only eleven patients (10.8 %) had portal branches originating from the TPLPV, with no impact on the number of branches coming from the UPLPV. Three patients (2.9 %) had one branch from the right portal vein. In patients with only two or three branches supplying S4, the branches had a larger diameter and typically arose from a short common trunk which divided further within its first centimetres.

Conclusions: Portal vascularization of S4 varies widely (2-8 branches) between patients and originates predominantly from the junction between the left portal vein and the round ligament. There is no anatomical rationale to divide S4 into S4a and S4b.
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http://dx.doi.org/10.1007/s00276-016-1761-3DOI Listing
May 2017

Time interval between surgery and start of adjuvant radiotherapy in patients with soft tissue sarcoma: A retrospective analysis of 1131 cases from the French Sarcoma Group.

Radiother Oncol 2016 07 17;120(1):156-62. Epub 2016 May 17.

Department of Radiation Oncology, Institut Bergonié, Bordeaux, France.

Purpose: The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS).

Methods And Materials: Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model.

Results: The median TI was 82days (range, 18-346). With a median follow-up of 235months (range, 2-296months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19-39days, 40-79days, 80-119days, and ⩾120days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% (p=0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% (p=0.347), respectively. After adjustment for the factors significantly (p⩽0.05) associated with LRFS and OS, TI did not alter LRFS (p=0.182) either OS (p=0.335).

Conclusions: In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes.
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http://dx.doi.org/10.1016/j.radonc.2016.04.037DOI Listing
July 2016

KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome.

BMC Cancer 2015 Oct 24;15:780. Epub 2015 Oct 24.

Department of medical oncology, Centre Leon Berard, 28 rue Laennec, Lyon, France.

Background: Tumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT may influence GIST patient outcome is unclear.

Methods: We investigated the biological and clinical significance of the presence of KIT exon 10 variant (c.1621 A > C), KIT (L541), in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion.

Results: In the 3 T3 L541 cell line, KIT(L541) protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22%) harboured KIT (L541), similarly to the control group of healthy donors (n = 10 of 60, 17%). A higher prevalence of the variant KIT (L541) was observed in patients with metastatic status at diagnosis (KIT (L541) correlated nine of 22 versus 15 of 87, p = 0.02). In addition, patients with KIT (L541) and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KIT (L541) and KIT (M541) patients.

Conclusion: KIT (L541) genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients.
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http://dx.doi.org/10.1186/s12885-015-1817-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619434PMC
October 2015