Publications by authors named "Jean Luc Raoul"

175 Publications

Anosmia but Not Ageusia as a COVID-19-Related Symptom among Cancer Patients-First Results from the PAPESCO-19 Cohort Study.

Cancers (Basel) 2021 Jul 6;13(14). Epub 2021 Jul 6.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, 44805 Saint-Herblain, France.

Cancer patients may fail to distinguish COVID-19 symptoms such as anosmia, dysgeusia/ageusia, anorexia, headache, and fatigue, which are frequent after cancer treatments. We aimed to identify symptoms associated with COVID-19 and to assess the strength of their association in cancer and cancer-free populations. The multicenter cohort study PAPESCO-19 included 878 cancer patients and 940 healthcare workers (HCWs). At baseline and quarterly thereafter, they reported the presence or absence of 13 COVID-19 symptoms observed over 3 months and the results of routine screening RT-PCR, and they were systematically tested for SARS-CoV-2-specific antibodies. We identified the symptom combinations significantly associated with COVID-19. Eight percent of cancer patients were COVID-19 positive, and 32% were symptomatic. Among the HCWs, these proportions were 9.5 and 52%, respectively. Anosmia, anorexia, fever, headache, and rhinorrhea together accurately discriminated (c-statistic = 0.7027) COVID-19 cases from cancer patients. Anosmia, dysgeusia/ageusia, muscle pain, intense fatigue, headache, and chest pain better discriminated (c-statistic = 0.8830) COVID-19 cases among the HCWs. Anosmia had the strongest association in both the cancer patients (OR = 7.48, 95% CI: 2.96-18.89) and HCWs (OR = 5.71, 95% CI: 2.21-14.75). COVID-19 symptoms and their diagnostic performance differ in the cancer patients and HCWs. Anosmia is associated with COVID-19 in cancer patients, while dysgeusia/ageusia is not. Cancer patients deserve tailored preventive measures due to their particular COVID-19 symptom pattern.
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http://dx.doi.org/10.3390/cancers13143389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303411PMC
July 2021

Expected outcomes and patients' selection before chemoembolization-"Six-and-Twelve or Pre-TACE-Predict" scores may help clinicians: Real-life French cohorts results.

World J Clin Cases 2021 Jun;9(18):4559-4572

Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13008, France.

Background: Careful selection of hepatocellular carcinoma (HCC) patients prior to chemoembolization treatment is a daily reality, and is even more necessary with new available therapeutic options in HCC.

Aim: To propose two new models to better stratify patients and maximize clinical benefit: "6 and 12" and "pre/post-TACE-predict" (TACE, transarterial chemoembolization).

Methods: We evaluated and compared their performance in predicting overall survival with other systems {Barcelona Clinic Liver Cancer (BCLC), Albumin-Bilirubin (ALBI) and NIACE [Number of tumor(s), Infiltrative HCC, alpha-fetoprotein, Child-Pugh (CP), and performance status]} in two HCC French cohorts of different stages enrolled between 2010 and 2018.

Results: The cohorts included 324 patients classified as BCLC stages A/B (cohort 1) and 137 patients classified as BCLC stages B/C (cohort 2). The majority of the patients had cirrhosis with preserved liver function. "Pre-TACE-predict" and "6 and 12" models identified three distinct categories of patients exhibiting different prognosis in cohort 1. However, their prognostic value was no better than the BCLC system or NIACE score. Liver function based on CP and ALBI grades significantly impacted patient survival. Conversely, the "post-TACE-predict" model had a higher predictive value than other models. The stratification ability as well as predictive performance of these new models in an intermediate/advanced stage population was less efficient (cohort 2).

Conclusion: The newly proposed "Pre-TACE-predict" and "6 and 12" models offer an interesting stratification into three categories in a recommended TACE population, as they identify poor candidates, those with partial control and durable response. The models' contribution was reduced in a population with advanced stage HCCs.
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http://dx.doi.org/10.12998/wjcc.v9.i18.4559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223847PMC
June 2021

Prevalence of Proton Pump Inhibitor Use Among Patients With Cancer.

JAMA Netw Open 2021 Jun 1;4(6):e2113739. Epub 2021 Jun 1.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.13739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209575PMC
June 2021

Transient Vision Loss - A Rare Oxaliplatin-Induced Ophthalmologic Side Effect: A Report of Two Cases.

Case Rep Oncol 2021 Jan-Apr;14(1):483-486. Epub 2021 Mar 18.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.

Oxaliplatin, a platinum-based chemotherapeutic agent, is responsible for induced peripheral sensory neuropathy. Only a few cases of ophthalmologic toxicity have been reported. We report here two cases of sudden transient vision loss after oxaliplatin administration, in one case intraperitoneally. These symptoms likely reflect optic neuritis that could be included in the spectrum of oxaliplatin-induced neuropathy.
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http://dx.doi.org/10.1159/000514656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077355PMC
March 2021

Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components.

Front Oncol 2021 31;11:646992. Epub 2021 Mar 31.

Predictive Oncology Laboratory, Department of Medical Oncology, CRCM, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.

Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?
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http://dx.doi.org/10.3389/fonc.2021.646992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092117PMC
March 2021

Efficacy of FOLFOX Chemotherapy in Metastatic Enteropancreatic Neuroendocrine Tumors.

Anticancer Res 2021 Apr;41(4):2071-2078

Department of Medical Oncology, ENETS Center of Excellence, IPC NET Center, Institut Paoli-Calmettes, Marseille, France.

Background/aim: FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX.

Patients And Methods: We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board.

Results: Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and F-FDG PET positivity.

Conclusion: FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs.
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http://dx.doi.org/10.21873/anticanres.14977DOI Listing
April 2021

Case Report: Two Cases of Metastatic Pancreatoblastoma in Adults: Efficacy of Folfirinox and Implication of the Wnt/β-Catenin Pathway in Genomic Analysis.

Front Oncol 2021 16;11:564506. Epub 2021 Mar 16.

Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.

Pancreatoblastomas are unfrequent tumors usually found in children. We report two cases of metastatic pancreatoblastomas observed in young women. A systemic chemotherapy (FOLFIRINOX regimen) was associated with a disease control in one case and a partial response in the second with an improvement of general status for both. A high-throughput sequencing of the tumor described in both cases alteration in the Wnt/β-catenin pathway: a mutation in (exon 3, c.110C>G, p.S37C, reported as a hotspot in COSMIC) in one case and a homozygous loss associated with breakage targeting (5q22.2) in the second.
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http://dx.doi.org/10.3389/fonc.2021.564506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007973PMC
March 2021

Retrorectal Mucinous Adenocarcinoma Arising from a Tailgut Cyst: A Case Report.

Case Rep Oncol 2021 Jan-Apr;14(1):147-151. Epub 2021 Mar 1.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.

We report the case of a 57-year-old woman who presented with local invasion of the anal canal by mucinous adenocarcinoma, the malignant transformation of a long-term preexisting retrorectal tailgut cyst. This progression is infrequent and justifies preemptive surgical treatment of retrorectal cysts.
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http://dx.doi.org/10.1159/000513028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983577PMC
March 2021

Radiosensitizing Chemotherapy (Irinotecan) with Stereotactic Body Radiation Therapy for the Treatment of Inoperable Liver and/or Lung Metastases of Colorectal Cancer.

Cancers (Basel) 2021 Jan 11;13(2). Epub 2021 Jan 11.

Department of Radiation Oncology, Institut de Cancérologie de l'Ouest, 44800 St-Herblain, France.

: Stereotactic body radiotherapy (SBRT) is a recognized treatment for colorectal cancer (CRC) metastases. We postulated that local responses could be improved by SBRT with a concomitant radiosensitizing agent (irinotecan). : RADIOSTEREO-CAMPTO was a prospective multi-center phase 2 trial investigating SBRT (40-48 Gy in 4 fractions) for liver and/or lung inoperable CRC oligometastases (≤3), combined with two weekly intravenous infusions of 40 mg/m Irinotecan. Primary outcome was the objective local response rate as per RECIST. Secondary outcomes were early and late toxicities, EORTC QLQ-C30 quality of life, local control and overall survival. : Forty-four patients with 51 lesions (liver = 39, lungs = 12) were included. Median age was 69 years (46-84); 37 patients (84%) had received at least two prior chemotherapy treatments. Median follow-up was 48.9 months. One patient with two lung lesions was lost during follow-up. Assuming maximum bias hypothesis, the objective local response rate in ITT was 86.3% (44/51-95% CI: [76.8-95.7]) or 82.4% (42/51-95% CI: [71.9-92.8]). The observed local response rate was 85.7% (42/49-95% CI: [75.9-95.5]). The 1 and 2-year local (distant) progression-free survivals were 84.2% (38.4%) and 67.4% (21.3%), respectively. The 1 and 2-year overall survivals were 97.5% and 75.5%. There were no severe acute or late reactions. The EORTC questionnaire scores did not significantly worsen during or after treatment. : SBRT with irinotecan was well tolerated with promising results despite heavily pretreated patients.
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http://dx.doi.org/10.3390/cancers13020248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827408PMC
January 2021

A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers.

Eur J Cancer 2020 11 8;140:37-44. Epub 2020 Oct 8.

Department of Surgical Oncology, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Objective: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers.

Methods: PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m with planned increases of 50 mg/m per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252).

Results: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m and two at 140 mg/m. The MTD was therefore set at 90 mg/m. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC) of 1035 μg/l and 9028 μg h/L, respectively.

Conclusions: The MTD of oxaliplatin during PIPAC is 90 mg/m. PK data demonstrate a high tumour concentration and a significant systemic absorption.
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http://dx.doi.org/10.1016/j.ejca.2020.09.010DOI Listing
November 2020

"Six-and-twelve" score for outcome prediction of hepatocellular carcinoma following transarterial chemoembolization. In-depth analysis from a multicenter French cohort.

World J Hepatol 2020 Aug;12(8):525-532

Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille 13008, France.

The "six-and-twelve" (6&12) score is a new hepatocellular carcinoma (HCC) prognostic index designed for recommended transarterial chemoembolization (TACE) candidates. Quick and easy to use by the sum of tumor size (cm) and number, this model identifies three groups with different survival time (the sum is ≤ 6; or > 6 but ≤ 12; or > 12); a survival benefit with TACE can be expected for HCC patients with a score not exceeding twelve. Recently, Wang ZW et al showed that the "6&12" model was the best system correlated with radiological response after the first TACE. Thus, we wanted to assess its survival prediction ability as well as its prognostic value and compared it to other systems (Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer (HKLC) staging, Albumin-Bilirubin grade, tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, Child-Pugh class, and Performance Status score, Cancer of the Liver Italian Program, Model to Estimate Survival for HCC scores, up-to-seven criteria) different from Wang ZW et al study in a multicenter French cohort of HCC including only recommended TACE candidates retrospectively enrolled. As previously demonstrated, we show that the "6&12" score can classify survival within this French cohort, with a prognostic value comparable to that of other systems, except HKLC staging. More importantly, the "6&12" score simplicity and ability in patients' stratification outperform other systems for a routine clinical practice.
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http://dx.doi.org/10.4254/wjh.v12.i8.525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475776PMC
August 2020

Intra-arterial hepatic beads loaded with irinotecan (DEBIRI) with mFOLFOX6 in unresectable liver metastases from colorectal cancer: a Phase 2 study.

Br J Cancer 2020 08 8;123(4):518-524. Epub 2020 Jun 8.

Département de Gastroentérologie et d'Oncologie Digestive, Hôpital Européen George Pompidou, Paris, France.

Background: Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection.

Methods: In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session.

Results: Fifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3).

Conclusions: Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal.

Clinical Trial Registration: NCT01839877.
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http://dx.doi.org/10.1038/s41416-020-0917-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435188PMC
August 2020

Systemic treatment of hepatocellular carcinoma: standard of care in China and elsewhere.

Lancet Oncol 2020 04 26;21(4):479-481. Epub 2020 Feb 26.

Medical Oncology, Centre Eugène Marquis, Rennes 35042, France.

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http://dx.doi.org/10.1016/S1470-2045(20)30082-6DOI Listing
April 2020

[Proton pump inhibitors and cancers: A hazardous association?]

Bull Cancer 2020 Apr 10;107(4):458-464. Epub 2020 Feb 10.

Institut de cancérologie de l'Ouest, département d'oncologie médicale, boulevard Professeur Jacques-Monod, 44800 Saint-Herblain, France.

Proton pump inhibitors, a major progress in gastro-enterology, are globally among the most widely prescribed drugs. But, due to their strong gastric acid inhibition, they can be responsible for side effects, particularly in cancer patients. They are involved in renal function impairment, bone fractures, digestive bacterial overgrowth, particularlyclostridium difficile infections, anemia and hypomagnesemia. Long term use can increase the risks of gastric, pancreatic and liver cancers. They decrease absorption of weak bases drugs, particularly tyrosine kinase inhibitors and capecitabine and are responsible for a poorer prognosis if taken concomitantly with erlotinib, gefitinib and pazopanib. Modification of cyclin dependent kinases is also possible as well as decrease of efficacy of immune check point inhibitors (microbiome modifications). Absoption and efficacy of capecitabine seem also poorer with negative prognosis effect on treatment of gastric and colon cancer. Their long term use, particularly in cancer patients, should probably be avoided.
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http://dx.doi.org/10.1016/j.bulcan.2019.12.009DOI Listing
April 2020

Sorafenib: Experience and Better Manage-ment of Side Effects Improve Overall Survival in Hepatocellular Carcinoma Patients: A Real-Life Retrospective Analysis.

Liver Cancer 2019 Nov 27;8(6):457-467. Epub 2019 Mar 27.

Department of Hepato-Gastroenterology, Hôpital Saint-Joseph, Marseille, France.

Background: Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). The management of its side effects is improving. This study aimed to assess, in real life, if this translates into a better prognosis.

Methods: This was a retrospective study of advanced HCC patients treated with sorafenib between 2007 and 2017.

Results: 188 advanced HCC patients received > 4 weeks of sorafenib. Median treatment duration was 5.4 months and median overall survival (mOS) 10 months (95% confidence interval 15-27). Sorafenib was initiated in 65 patients in 2007-2012 and 123 in 2013-2017. Both groups were comparable except for Barcelona Clinic liver cancer class. Tumor progression, disease control (DC) rate, and incidence of toxicity were similar in the 2 periods, but the duration of treatment (4.3 vs. 5.9 months; < 0.01) and mOS (8 vs. 12 months; < 0.002) differed. Among progressive disease patients, mOS was similar (7 months) but for those who had DC at 8 weeks, mOS was longer in the recent period (13 vs. 27 months; < 0.0001). In the univariate analysis of OS, the period of treatment had a prognostic value.

Conclusion: When comparing 2 periods of treatment in advanced HCC patients under sorafenib, duration of treatment and mOS were higher in the recent period. While mOS did not differ for patients who progressed, it was 2-fold higher in the recent period for those who had tumor control. Improvements in the use of sorafenib seem to be associated with better outcomes limited to patients with DC.
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http://dx.doi.org/10.1159/000497161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883434PMC
November 2019

Intra-abdominal recurrence from colorectal carcinoma: Differences and similarities between local and peritoneal recurrence.

Surg Oncol 2020 Mar 4;32:23-29. Epub 2019 Nov 4.

Department of Surgical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de l'Ouest, France.

Background: Peritoneal recurrences from colo-rectal cancer can be isolated (PR) or associated with local recurrences (LR). The purpose of this study was to analyze patterns and outcomes of LR and PR.

Methods: Analyze from a prospective database of 108 patients treated with CCS plus HIPEC at two cancer centers between 2008 and 2015.

Results: The population was divided into an LPR group (presence of LR with or without PR, n = 56) and a PR group (isolated PR, n = 52). The patients characteristics (age, sex, Charlson score, PCI) or perioperative treatments were comparable between the groups. The median number of resected organs for tumor involvement (respectively, 2 vs 1; p < 0.001), the percentage of patients with metastatic lymph nodes (LN+) from the resected specimen (respectively, 25% vs 7%; p = 0.016) and the mortality rate (respectively, 9% vs 0%; p = 0.023) were significantly higher in the LPR group. After a median follow-up of 32 (1-108) months, median overall survival was comparable between the two groups (respectively, 46 vs 42 months; p = 0.262).

Conclusions: LR is associated with a higher incidence of organ invasion, LN involvement (25%) and postoperative mortality. Optimal surgical resection of LR with systematic lymphadenectomy of invaded organs seems mandatory.
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http://dx.doi.org/10.1016/j.suronc.2019.10.018DOI Listing
March 2020

Prognostication of HCC under sorafenib: Is it always possible?

Liver Int 2020 05 26;40(5):1241-1243. Epub 2019 Nov 26.

Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph Marseille, Marseille, France.

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http://dx.doi.org/10.1111/liv.14294DOI Listing
May 2020

Significance of lymph node involvement in local recurrence of colorectal cancer.

J Surg Oncol 2019 Sep 22;120(4):722-728. Epub 2019 Jul 22.

Department of Surgical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.

Background: There are few data on lymphatic spread concomitant to local recurrence (LR) of colorectal cancer (CRC). The objectives of this study were to determine variables associated with lymphatic spread, to analyze the distribution of LN+, and understand the underlying mechanisms.

Methods: A total of 76 patients underwent resection of LR of CRC between January 2007 and December 2018 at Institut cancérologique de l'Ouest and were retrospectively reviewed.

Results: Twenty-five (32.9%) patients had lymph node (LN) involvement with LR. Lymphatics from the mesocolon-rectum and aorto-iliac compartments were involved in 21%, 20.3% and 18.1%, 20.3% for pelvic and retroperitoneal LRs, respectively. In multivariate analysis, the only predictive factor for LN invasion (LN+) was a primary positive LN status (odds ratio, 5.3; P = .007). Despite a trend toward a worse median overall survival in the LN+ group, the difference was not significant in comparison with the LN- group (46 vs. 57 months; P = 0.31) or with the LN- plus LN not assessed groups (46 months vs not reached; P = .07).

Conclusions: LN invasion with LR from CRC is a frequent occurrence without significant impact on survival. The only predictive factor is a primary positive nodal status.
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http://dx.doi.org/10.1002/jso.25631DOI Listing
September 2019

Current options and future possibilities for the systemic treatment of hepatocellular carcinoma.

Hepat Oncol 2019 Jun 4;6(1):HEP11. Epub 2019 Jun 4.

Department of Medical Oncology, Institut Paoli-Calmettes, Cedex 9, Marseille 13000, France.

Most hepatocellular carcinoma patients could not benefit from or experience disease recurrence after curative treatments. In 2007 sorafenib demonstrated efficacy in first line treatment of advanced hepatocellular carcinoma. After a decade of negative trials, in early 2019 we now have another tyrosine kinase inhibitor available in first line, lenvatinib, three other targeted therapies in second line post-sorafenib (regorafenib, cabozantinib and ramucirumab) and promising data from two immunotherapies (nivolumab and pembrolizumab). Unfortunately, no biomarkers have been identified to help guide our choice. In this short review we summarize the results of these different therapies and propose a therapeutic algorithm based on subgroup analysis. It is most likely that we will not have head-to-head comparisons in second line trials.
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http://dx.doi.org/10.2217/hep-2019-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571544PMC
June 2019

BRAF Non-V600E Mutated Metastatic Colorectal Cancer in a Young Patient: Discussion from a Case Report.

Case Rep Oncol 2019 May-Aug;12(2):426-429. Epub 2019 Jun 5.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.

We report the case of a 32-year-old man with a caecal adenocarcinoma with major lymph node extension and peritoneal carcinomatosis, presenting a BRAF-K601E mutation. A triplet (5FU plus oxaliplatin plus irinotecan) combination with bevacizumab achieved tumor control but the disease progressed immediately after cessation and the patient died 8 months after the diagnosis. A short review of BRAF non-V600E mutations shows that outcome and clinical features depend on the mutation.
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http://dx.doi.org/10.1159/000500857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587192PMC
June 2019

Sensitive and easy screening for circulating tumor cells by flow cytometry.

JCI Insight 2019 06 13;5. Epub 2019 Jun 13.

Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France.

Circulating Tumor Cells (CTCs) represent an easy, repeatable and representative access to information regarding solid tumors. However, their detection remains difficult because of their paucity, their short half-life, and the lack of reliable surface biomarkers. Flow cytometry (FC) is a fast, sensitive and affordable technique, ideal for rare cells detection. Adapted to CTCs detection (i.e. extremely rare cells), most FC-based techniques require a time-consuming pre-enrichment step, followed by a 2-hours staining procedure, impeding on the efficiency of CTCs detection. We overcame these caveats and reduced the procedure to less than one hour, with minimal manipulation. First, cells were simultaneously fixed, permeabilized, then stained. Second, using low-speed FC acquisition conditions and two discriminators (cell size and pan-cytokeratin expression), we suppressed the pre-enrichment step. Applied to blood from donors with or without known malignant diseases, this protocol ensures a high recovery of the cells of interest independently of their epithelial-mesenchymal plasticity and can predict which samples are derived from cancer donors. This proof-of-concept study lays the bases of a sensitive tool to detect CTCs from a small amount of blood upstream of in-depth analyses.
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http://dx.doi.org/10.1172/jci.insight.128180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675556PMC
June 2019

FOLFOX alone or combined with rilotumumab or panitumumab as first-line treatment for patients with advanced gastroesophageal adenocarcinoma (PRODIGE 17-ACCORD 20-MEGA): a randomised, open-label, three-arm phase II trial.

Eur J Cancer 2019 07 23;115:97-106. Epub 2019 May 23.

Department of Hepatogastroenterology and Gastrointestinal Oncology, Hôpital Européen Georges Pompidou, Paris, Sorbonne Paris Cité, Paris Descartes University, France.

Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma.

Patients And Methods: This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil 400 mg/m bolus then 2400 mg/m over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance.

Results: The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%).

Conclusions: We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinoma patients.

Trial Registration: European Clinical Trials Database, number 2009-012797-12.
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http://dx.doi.org/10.1016/j.ejca.2019.04.020DOI Listing
July 2019

Hepatocellular carcinoma macroscopic gross appearance on imaging: predictor of outcome after transarterial chemoembolization in a real-life multicenter French cohort.

Eur J Gastroenterol Hepatol 2019 Nov;31(11):1414-1423

Department of Gastroenterology and Hepatology.

Background: Conventional transarterial chemoembolization (cTACE) with lipiodol is widely performed in patients with hepatocellular carcinoma (HCC) unsuitable for curative treatment. Additional tumor parameters such as HCC macroscopic appearance based on imaging might be helpful for transarterial chemoembolization prognostication and management.

Patients And Methods: A total of 405 patients with HCC who underwent cTACE between 2008 and 2016 from a real-life multicenter French cohort were retrospectively reviewed. Tumors were classified into two macroscopic types according to HCC gross appearance on imaging: nodular versus non-nodular. The study population was stratified into two groups: derivation and validation cohorts. Independent prognostic factors of survival based on multivariate cox regression models were determined and then assessed in the validation set. Thereafter, time to progression (TTP) and radiological response rate were investigated for each prognostic factors of survival.

Results: Median overall survival (OS) was 35 months for Barcelona Clinic Liver Cancer (BCLC) stage A, 22 months for BCLC stage B and 12 months for BCLC stage C patients (P < 0.0001). The corresponding TTP for these patients was 12 (7-17) months, 5 (3-6) months and 1.2 (1.2-3) months (P < 0.0001). Multivariate analysis revealed that tumors size and number, non-nodular type, alpha-fetoprotein, aspartate aminotransferase serum levels and impairment of performance status-1 were independent predictors of survival among the study groups. Non-nodular type was the most powerful factor that influences OS, TTP and radiological response rate for the recommended transarterial chemoembolization candidates. TTP was consistent with OS within each stage.

Conclusion: HCC macroscopic appearance on imaging is a determinant predictor of outcome after cTACE in a real-life multicenter cohort.
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http://dx.doi.org/10.1097/MEG.0000000000001420DOI Listing
November 2019

FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.

N Engl J Med 2018 12;379(25):2395-2406

From the Institut de Cancérologie de Lorraine and Université de Lorraine (T.C.) and Centre Hospitalier Universitaire (L.C.), Nancy, Hôpital Beaujon and University Paris VII, Clichy (P.H., A.S.), Hôpital Huriez, Lille (M.H.), Centre Paul Strauss, Strasbourg (M.B.A.), Institut Paoli-Calmettes, Marseille (J.-L.R.), Centre Antoine-Lacassagne, Nice (E.F.), Hôpital Jean-Mermoz, Lyon (P.A.), Hôpital Trousseau, Tours (T.L.), Centre Hospitalier Universitaire de Saint-Eloi (E.A.) and Institut du Cancer de Montpellier-Val d'Aurelle, Université de Montpellier (M.Y., S.G., F.C.), Montpellier, Centre Hospitalier Départemental Vendée, La Roche-sur-Yon (R.F.), Centre Hospitalier Universitaire Robert Debré, Reims (J.V.), Hôpital Louis Pasteur, Colmar (G.B.), Normandie University, Rouen University Hospital, Rouen (F.D.F.), Hôpital Layné, Mont-de-Marsan (P.T.), Centre Hospitalier Universitaire Côte de Nacre, Caen (K.B.-L.), Hôpital Saint-Jean, Perpignan (F.K.-A.), Centre Hospitalier Régional, Orléans (J.-L.L.), R&D Unicancer (B.J., C.J.-Z.) and Sorbonne Université, Hôpitaux Universitaires Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris (J.-B.B.), Paris, Gustave Roussy, Université Paris-Saclay, Villejuif (D.M.), and Centre Hospitalier Universitaire, Dijon (P.R.) - all in France; and the Princess Margaret Cancer Centre, Toronto (A.C.W.), Kingston General Hospital (J.J.B.) and the Canadian Cancer Trials Group, Queen's University (C.J.O.), Kingston, ON, the Ottawa Health Research Institute, Ottawa (C.C.), and Segal Cancer Centre, Jewish General Hospital, Montreal (P.K.) - all in Canada.

Background: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.

Methods: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety.

Results: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis).

Conclusions: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).
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http://dx.doi.org/10.1056/NEJMoa1809775DOI Listing
December 2018

Potential of ramucirumab in treating hepatocellular carcinoma patients with elevated baseline alpha-fetoprotein.

J Hepatocell Carcinoma 2018 2;5:91-98. Epub 2018 Nov 2.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest René Gauducheau, 44805 Nantes, France.

Hepatocellular carcinoma (HCC) represents ~90% of primary liver cancers and constitutes a major global health problem. Since a decade ago, the management of advanced disease that cannot be locally treated has mainly been based on multi-targeted antiangiogenic therapies. Some have demonstrated improvement in overall survival over best supportive care in first- and second-line treatment. This study focused on the efficacy of antiangiogenics in patients with advanced HCC and particularly the rising role of ramucirumab in patients with elevated alpha-fetoprotein at diagnosis.
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http://dx.doi.org/10.2147/JHC.S157413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219272PMC
November 2018

Patients with resectable pancreatic adenocarcinoma: A 15-years single tertiary cancer center study of laparotomy findings, treatments and outcomes.

Surg Oncol 2018 Dec 3;27(4):619-624. Epub 2018 Aug 3.

Department of Digestive Surgery, Paoli-Calmettes Institute, 13232, Marseille Cedex 9, France.

Background: To describe, in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the laparotomy findings, treatments and outcomes before (period 1) and after 2010 (period 2).

Methods: From 2000 to 2015, patients newly diagnosed with resectable PDAC at Paoli-Calmettes Institute, France, were evaluated. Survival was examined using the Kaplan-Meier method, and statistical comparisons were conducted using log rank tests.

Results: Among 1175 patients diagnosed with pancreatic mass, 164 underwent laparotomy with an intention of pancreatic resection. Some of them did not undergo pancreatic resection due to peroperative discovery of advanced disease. For those who were finally resected (n = 119), there were fewer pancreaticoduodenectomies (p = 0.045), shorter operation times (p < 0.01), lower mortality rates (p = 0.02), more advanced-stage tumors (T3), more frequent perineural invasion and R1 resection in period 2. This group had a trend of better outcomes after 2010 (51 months vs. 36 months (p = 0.065)).

Conclusion: Improvement in surgical procedures and postoperative management led to prolonged survival of those who underwent surgery for resectable pancreatic cancer since 2010, despite a higher frequency of advanced tumors at the diagnosis in our institution.
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http://dx.doi.org/10.1016/j.suronc.2018.07.014DOI Listing
December 2018

Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence.

Cancer Treat Rev 2019 Jan 12;72:28-36. Epub 2018 Nov 12.

Gustave Roussy-Cancer Campus, rue Edouard-Vaillant 114, 94 805 Villejuif Cedex, France. Electronic address:

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, representing the sixth leading cause of cancer and the third leading cause of cancer-related mortality. Patient stratification and treatment allocation are based on tumor stage, liver function, and performance status. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate stage HCC, including those with large or multinodular HCC, well-preserved liver function, and no cancer-related symptoms or evidence of vascular invasion or extrahepatic spread. Two TACE techniques have been used since 2004, conventional TACE (cTACE) and TACE with drug-eluting beads (DEB-TACE). cTACE was evidenced first to treat intermediate stage HCC patients. It combines the transcatheter delivery of chemotherapy using Lipiodol-based emulsion plus an embolizing agent to achieve strong cytotoxic and ischemic effects. Drug-eluting beads (DEBs) were developed in order to slowly release chemotherapeutic agents, and to increase ischemia intensity and duration. Recent advances allow TACE treatment of both early stage patients (i.e. those with a solitary nodule or up to 3 nodules under 3 cm) and some advanced stage patients. Here we review recent clinical evidence related to TACE treatment of patients with early, intermediate, and advanced stage HCC. Based on the 2014 TACE algorithm of Raoul et al., this international expert panel proposes an updated TACE algorithm and provides insights into TACE use for patients at any HCC stage.
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http://dx.doi.org/10.1016/j.ctrv.2018.11.002DOI Listing
January 2019

Characterization of subepithelial lesions of the stomach and esophagus by contrast-enhanced EUS: A retrospective study.

Endosc Ultrasound 2019 Jan-Feb;8(1):43-49

Endoscopic Unit, Paoli Calmettes Institute, Marseille, France.

Background And Objectives: Subepithelial lesions (SELs) of the upper part of the digestive tract are rare, and it can be difficult to characterize them. Recently, contrast-enhanced endosonography (EUS) and elastometry have been reported as useful adjuncts to EUS and EUS-guided fine needle aspiration (EUS-FNA) in cases of pancreatic mass and lymph node involvement. The aim of this retrospective analysis was to evaluate whether contrast-enhanced EUS can discriminate benign submucosal lesions from malignant ones. We describe our retrospective experience using the contrast agent SonoVue (Bracco Imaging, Milan, Italy) in an attempt to increase the diagnostic yield.

Patients And Methods: Between May 2011 and September 2014, 14 patients (5 men, 9 women; median age 64 years, range 31-80 years) with SELs of the stomach or esophagus underwent EUS with SonoVue (low mechanical index). There were 3 esophageal lesions and 11 gastric lesions. Mean size of the lesions was 30 mm (range 11-50 mm). They were discovered after anemia (n = 5), dysphagia (n = 1), and pain (n = 4) and during follow-up for resected gastrointestinal stromal tumors (GISTs) (n = 1) and a standard upper gastrointestinal endoscopy (n = 3). On endoscopic sonograms, 10 of these lesions were hypoechoic and located in the fourth layer (muscularis), and 4 were in the second or third layer (mucosa and submucosa). Contrast enhancement was assessed in the early phase (after several seconds) and late phase (>30 seconds); a final diagnosis was made based on the findings of EUS-FNA using a 19-gauge ProCore (Cook Medical, Bloomington, IN) (n = 9) or 22-gauge FNA system (Cook Medical) (n = 1), the resected specimen (n = 3), or deep biopsy (n = 1). Different immunostaining was used in the pathologic studies (RNA was analyzed later using the C-kit, CD-117, CD-34, desmin, DOG-1, α-smooth actin, caldesmon, PS-100, and Ki-67 antibodies).

Results: Final diagnoses were leiomyoma (n = 4), GIST (n = 5), schwannoma (n = 1), inflammatory tumor of Helvig (n = 1), pancreas rest (n = 2), and fibrosis (n = 1). No complications occurred. All 5 GISTs showed enhancement in the early and late phases, whereas the 8 remaining lesions did not show any enhancement. Only 1 leiomyoma showed heterogeneous enhancement.

Limitations: The monocentric and retrospective study design and small number of patients.

Conclusions: In cases of SELs of the stomach or esophagus, SonoVue could be a complementary tool to endosonography to differentiate GISTs (early and clear enhancement) from other SELs (few or no enhancement), such as leiomyomas or pancreatic rest. These results are similar to those of the few, small studies published on this topic, but more studies with a larger number of patients are needed to confirm these findings.
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http://dx.doi.org/10.4103/eus.eus_89_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400084PMC
September 2018

Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond.

Cancer Treat Rev 2018 Jul 26;68:16-24. Epub 2018 May 26.

I. Medical Department, Mainz University Medical Center, Langenbeckstraße 1, 55131 Mainz, Germany. Electronic address:

The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.
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http://dx.doi.org/10.1016/j.ctrv.2018.05.006DOI Listing
July 2018
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