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1. Capecitabine/Mitomycin versus 5-Fluorouracil/Mitomycin in Combination with Simultaneous Integrated Boost Intensity-Modulated Radiation Therapy for Anal Cancer

Author

Laurent Mineur, Léa Vazquez, Mohamed Belkacemi, Clémence Toullec, Newfel Bentaleb, Rania Boustany, and Frederi Plat

Subjects
anal cancer, capecitabin, 5-FU, radiation therapy, toxicity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Since EXTRA, a non-randomized phase II trial with 31 patients, explored the use of capecitabine, mitomycin and radiation therapy (RT) in the treatment of localized squamous cell carcinoma of the anal canal (SCCAC), this treatment has been considered as an acceptable alternative to infusional 5-FU. However, the differences in efficacy between capecitabine and 5-FU in chemoradiation therapy (CRT) with simultaneous integrated boost (SIB) radiation therapy (SIB-IMRT) for local SCCAC are not well documented. Patients included in this prospective monocentric cohort study were treated with SIB-RapidArc (a unique RT method treatment for all patients: identical technique, volume and constraints for at-risk organs), mitomycin C and 5-FU each day of RT for 7 weeks (group 1) or capecitabine each day of RT (group 2). Patients treated between July 2009 and August 2017 (group 1) and between November 2012 and April 2018 (group 2) for local SCCAC T2-4 classified as N, M0 or T, N1-3, M0 were included. Primary endpoints were progression-free survival (PFS) and acute toxicities. Results: One hundred forty-seven patients were included, 91 in group 1 and 56 in group 2. The two groups were statistically comparable in terms of sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and TNM. With a median duration of follow-up of 53.5 months, the PFS rate at 3 years was 80% for group 1 and 75% for group 2 (p = 0.32). The 3-year colostomy-free survival rate was 92% for group 1 and 85% for group 2 (p = 0.11). The rate of patients with at least one grade 3 or higher acute toxicity was 35.5% in group 1 and 21.4% in group 2 (p = 0.10), with a trend of fewer acute toxicities with capecitabine. Conclusion: Capecitabine/mitomycin in combination with SIB RapidArc radiation therapy for anal cancer seems as effective as 5-FU-based chemotherapy and is well tolerated with minimal toxicity.

Published
2023
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2. TACE and conformal radiotherapy vs. TACE alone for hepatocellular carcinoma: A randomised controlled trial

Author

Cyrille Féray, Loic Campion, Philippe Mathurin, Isabelle Archambreaud, Xavier Mirabel, Jean Pierre Bronowicki, Emmanuel Rio, Christophe Perret, Laurent Mineur, Frédéric Oberti, Yann Touchefeu, Jérôme Gournay, Hélène Regnault, Julien Edeline, Agnès Rode, Patrick Hillion, Jean Frédéric Blanc, Eric Nguyen Khac, Daniel Azoulay, Alain Luciani, Athena Galetto Preglisasco, Elodie Faurel-Paul, Hélène Auble, Françoise Mornex, and Philippe Merle

Subjects
Hepatocellular carcinoma, Conformal external radiotherapy, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Transcatheter arterial chemoembolisation (TACE) is recommended for patients with hepatocellular carcinoma devoid of macrovascular invasion or extrahepatic spread but not eligible for curative therapies. We compared the efficacy and safety of the combination of a single TACE and external conformal radiotherapy (CRT) vs. classical TACE. Methods: TACERTE was an open-labelled, randomised controlled trial with a 1:1 allocation rate to two or three TACE (arm A) or one TACE + CRT (arm B). Participants had a mean age of 70 years, and 86% were male. The aetiology was alcohol in 85%. The primary endpoint was liver progression-free survival (PFS) in the intention-to-treat population. The typical CRT schedule was 54 Gy in 18 sessions of 3 Gy. Results: Of the 120 participants randomised, 64 were in arm A and 56 in arm B; 100 participants underwent the planned schedule and defined the ‘per-protocol’ group. In intention-to-treat participants, the liver PFS at 12 and 18 months were 59% and 19% in arm A and 61% and 36% in arm B (hazard ratio [HR] 0.69; 95% CI 0.40–1.18; p = 0.17), respectively. In the per-protocol population, treated liver PFS tended to be better in arm B (HR 0.61; 95% CI 0.34–1.06; p = 0.081) than in arm A. Liver-related grade III–IV adverse events were more frequent in arm B than in arm A. Median overall survival reached 30 months (95% CI 23–35) in arm A and 22 months (95% CI 15.7–26.2) in arm B. Conclusions: Although TACE + CRT tended to improve local control, this first Western randomised controlled trial showed that the combined strategy failed to increase PFS or overall survival and led more frequently to liver-related adverse effects. Impact and implications: Hepatocellular carcinoma is frequently treated by arterial embolisation of the tumour and more recently by external radiotherapy. We tried to determine whether combination of the two treatments (irradiation after embolisation) might produce interesting results. Our results in this prospective randomised study were not able to demonstrate a beneficial effect of combining embolisation and irradiation in these patients. On the contrary, we observed more adverse effects with the combined treatment. Clinical Trials Registration: NCT01300143.

Published
2023
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3. Paraneoplastic Cushing Syndrome in Gastrointestinal Neuroendocrine Tumour

Author

Laurent Mineur, Rania Boustany, and Léa Vazquez

Subjects
ectopic cushing syndrome, neuroendocrine tumours, who grade 1, paraneoplastic syndromes, chromogranin a, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient’s prognosis and quality of life.

Published
2021
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4. Impact of Primary Tumour Location and Early Tumour Shrinkage on Outcomes in Patients with RAS Wild-Type Metastatic Colorectal Cancer Following First-Line FOLFIRI Plus Panitumumab

Author

Claus-Henning Köhne, Meinolf Karthaus, Laurent Mineur, Josef Thaler, Marc Van den Eynde, Javier Gallego, Reija Koukakis, Marloes Berkhout, and Ralf-Dieter Hofheinz

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Objective Data from a trial of first-line panitumumab plus FOLFIRI (folinic acid, infusional 5-fluorouracil and irinotecan) in metastatic colorectal cancer were retrospectively analysed to investigate the effects of primary tumour location and early tumour shrinkage on outcomes. Methods Patients with RAS wild-type metastatic colorectal cancer from a single-arm, open-label phase II study (NCT00508404) were included. Tumours located from the splenic flexure to rectum and in the caecum to transverse colon were defined as left- and right-sided, respectively. Baseline characteristics were summarised by primary tumour location and the effects of primary tumour location on outcomes—including objective response rate, resection rate, depth of response, duration of response and progression-free survival—were analysed. Progression-free survival and objective response rate were analysed by early tumour shrinkage status. Results Primary tumour location was determined in 52/69 (75%) patients with RAS wild-type metastatic colorectal cancer; 45 (87%) had left-sided disease. Median progression-free survival was longer in patients with left-sided tumours (11.2 vs. 7.2 months for right-sided disease) and more of these patients experienced early tumour shrinkage ≥ 30% (53% vs. 29%). Early tumour shrinkage ≥ 30% was associated with improved progression-free survival irrespective of tumour location. More patients with early tumour shrinkage ≥ 30% achieved a partial or complete response. Objective response rate, duration of response, depth of response and resection rates were similar in patients with left- and right-sided tumours. Conclusions This analysis has confirmed a prognostic effect of primary tumour location in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab plus FOLFIRI. Early tumour shrinkage was associated with improved progression-free survival irrespective of tumour location. In right-sided disease, early tumour shrinkage may identify a subgroup of patients who might respond to panitumumab. ClinicalTrials.gov identifier NCT00508404.

Published
2019
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5. 337 Pembrolizumab in combination with xelox bevacizumab in patients with microsatellite stable (MSS) metastatic colorectal cancer and a high immune infiltrate: a proof of concept study. FFCD 1703 POCHI

Author

Come Lepage, Harry Sokol, Julien Taieb, Thierry Lecomte, Vincent Hautefeuille, Romain Coriat, David Tougeron, Laétitia Dahan, Pierre Laurent-Puig, Jean Francois Emile, Stephano Kim, Carole Monterymard, Marine Gilabert, BEZ Jérémie, Astrid Lievre, Laurent Mineur, Jean Louis Legoux, Jean marc Phelip, Claude Capron, Claire Gallois, and Violaine Randrian

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2020
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6. Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer

Author

David Fogelman, Antonio Cubillo, Pilar García‐Alfonso, María Luisa Limón Mirón, John Nemunaitis, Daniel Flora, Christophe Borg, Laurent Mineur, Jose M. Vieitez, Allen Cohn, Gene Saylors, Albert Assad, Julie Switzky, Li Zhou, and Johanna Bendell

Subjects
clinical trial, colorectal cancer, inflammation, JAK1 protein tyrosine kinase, JAK2 protein tyrosine kinase, ruxolitinib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The Janus kinase/signal transducer and activator of transcription (JAK‐STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. Methods In this two‐part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0‐2; received fluoropyrimidine, oxaliplatin, and irinotecan‐based chemotherapy, an anti‐vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild‐type (and no contraindication), an anti‐epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open‐label, safety run‐in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double‐blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C‐reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). Results The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run‐in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression‐free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725‐1.492]; PFS: HR = 1.004 [0.724‐1.391]) and substudy 2 (OS: HR = 0.767 [0.478‐1.231]; PFS: HR = 0.787 [0.576‐1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. Conclusions Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.

Published
2018
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7. Panitumumab use in metastatic colorectal cancer and patterns of RAS testing: results from a Europe-wide physician survey and medical records review

Author

J. Han van Krieken, George Kafatos, James Bennett, Laurent Mineur, Jiří Tomášek, Etienne Rouleau, Pavel Fabian, Giovanna De Maglio, Pilar García-Alfonso, Giuseppe Aprile, Parijan Parkar, Gerald Downey, Gaston Demonty, and Jörg Trojan

Subjects
Panitumumab, Metastatic colorectal cancer, mCRC, RAS, Physician survey, Medical records review, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies – a physician survey and a medical records review (MRR) – were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice. Methods Both studies enrolled participants from nine European countries and were carried out in three consecutive rounds. Rounds 1 and 2 (2012–2013) examined KRAS (exon 2) testing only; the results have been published in full previously. Round 3 (2014–2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiring KRAS alone to requiring full RAS testing. For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab to patients with mCRC in the previous 6 months. For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients’ records. Results In Round 3, 152 oncologists and 131 patients’ records were included in the physician survey and MRR, respectively. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that panitumumab should only be prescribed in RAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmed KRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only). Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only. Conclusions Physicians’ adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, from KRAS to RAS wild-type mCRC. Additionally, this study demonstrates the uptake of full RAS testing among the majority of oncologists and pathologists.

Published
2017
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8. Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

Author

François-Clément Bidard, Nicolas Kiavue, Marc Ychou, Luc Cabel, Marc-Henri Stern, Jordan Madic, Adrien Saliou, Aurore Rampanou, Charles Decraene, Olivier Bouché, Michel Rivoire, François Ghiringhelli, Eric Francois, Rosine Guimbaud, Laurent Mineur, Faiza Khemissa-Akouz, Thibault Mazard, Driffa Moussata, Charlotte Proudhon, Jean-Yves Pierga, Trevor Stanbury, Simon Thézenas, and Pascale Mariani

Subjects
circulating tumor cells, circulating tumor DNA, liquid biopsy, metastatic colorectal cancer, FOLFIRINOX, Cytology, QH573-671
Abstract

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

Published
2019
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9. Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review.

Author

Jörg Trojan, Laurent Mineur, Jiří Tomášek, Etienne Rouleau, Pavel Fabian, Giovanna de Maglio, Pilar García-Alfonso, Giuseppe Aprile, Aliki Taylor, George Kafatos, Gerald Downey, Jan-Henrik Terwey, and J Han van Krieken

Subjects
Medicine, Science
Abstract

From 2008-2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported.The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey.In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme.There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.

Published
2015
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11. Bevacizumab plus FOLFIRI after failure of platinum–etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial

Author

Thomas Walter, Astrid Lievre, Romain Coriat, David Malka, Farid Elhajbi, Fréderic Di Fiore, Olivia Hentic, Denis Smith, Vincent Hautefeuille, Guillaume Roquin, Marine Perrier, Laetitia Dahan, Victoire Granger, Iradj Sobhani, Laurent Mineur, Patricia Niccoli, Eric Assenat, Jean-Yves Scoazec, Karine Le Malicot, Côme Lepage, and Catherine Lombard-Bohas

Subjects
Oncology
Published
2023

12. Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching

Author

Xavier, Adhoute, Marie, De Matharel, Laurent, Mineur, Guillaume, Pénaranda, Dann, Ouizeman, Clemence, Toullec, Albert, Tran, Paul, Castellani, Armelle, Rollet, Valérie, Oules, Hervé, Perrier, Si Nafa, Si Ahmed, Marc, Bourliere, and Rodolphe, Anty

Subjects
Oncology, Gastroenterology
Abstract

Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available.To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time.A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups.Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ)This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.

Published
2022

13. Supplementary Data 6 from Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author

Pierre Laurent-Puig, Jérôme Cros, Jason Cain, Camille Bourreau, Claire Mulot, Jean-Philippe Metges, Laurent Mineur, Fabienne Portales, Iman El Hariry, Pascal Hammel, Hélène Blons, and Jean-Baptiste Bachet

Abstract

Evolution of the maximal variant allelic fraction during the first three cycles in the 40 patients with all three available points.

Published
2023

14. Supplementary Data 5 from Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author

Pierre Laurent-Puig, Jérôme Cros, Jason Cain, Camille Bourreau, Claire Mulot, Jean-Philippe Metges, Laurent Mineur, Fabienne Portales, Iman El Hariry, Pascal Hammel, Hélène Blons, and Jean-Baptiste Bachet

Abstract

Description of patients' characteristics according to tertiles of ctDNA VAF frequency at baseline

Published
2023

17. Supplementary Data 2 from Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author

Pierre Laurent-Puig, Jérôme Cros, Jason Cain, Camille Bourreau, Claire Mulot, Jean-Philippe Metges, Laurent Mineur, Fabienne Portales, Iman El Hariry, Pascal Hammel, Hélène Blons, and Jean-Baptiste Bachet

Abstract

Figure S2a: Overall survival of patients with or without at least one available plasma sample. Figure S2b: Overall survival curves according to treatment arms for the 122 patients with at least one available plasma sample. Figure S2c: Progression free survival curves according to treatment arms for the 122 patients with at least one available plasma sample.

Published
2023

18. Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial

Author

Pierre Laurent-Puig, Thierry André, Dewi Vernerey, Aimery de Gramont, Thibault Mazard, Kariman Chaba, Katia Hormigos, Claire Mulot, Olivier Bouche, Joëlle Egreteau, May Mabro, Céline Lepere, Christophe Louvet, Jérôme Desrame, Jaafar Bennouna, Laurent Mineur, Camille Bourreau, Julie Henriques, Valérie Taly, and Julien Taieb

Abstract

Purpose:Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.Experimental Design:ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).Results:Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.Conclusions:In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.See related commentary by Bent and Kopetz, p. 5449

Published
2023

20. Supplementary Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial

Author

Pierre Laurent-Puig, Thierry André, Dewi Vernerey, Aimery de Gramont, Thibault Mazard, Kariman Chaba, Katia Hormigos, Claire Mulot, Olivier Bouche, Joëlle Egreteau, May Mabro, Céline Lepere, Christophe Louvet, Jérôme Desrame, Jaafar Bennouna, Laurent Mineur, Camille Bourreau, Julie Henriques, Valérie Taly, and Julien Taieb

Abstract

Supplementary Data

Published
2023

21. Supplementary Data 7 from Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author

Pierre Laurent-Puig, Jérôme Cros, Jason Cain, Camille Bourreau, Claire Mulot, Jean-Philippe Metges, Laurent Mineur, Fabienne Portales, Iman El Hariry, Pascal Hammel, Hélène Blons, and Jean-Baptiste Bachet

Abstract

Interaction between the presence of ctDNA at baseline and eryaspase efficacy on PFS and OS

Published
2023

22. Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49

Author

Simon Pernot, Olivier Pellerin, Laurent Mineur, Carole Monterymard, Denis Smith, Bruno Lapuyade, Claire Gallois, Faiza Khemissa Akouz, Thierry De Baere, David Tougeron, Anne Thirot-Bidault, Franck Audemar, Mireille Simon, Cedric Lecaille, Sami Louafi, Come Lepage, Michel Ducreux, and Julien Taieb

Subjects
Organoplatinum Compounds, Hepatology, Liver Neoplasms, Leucovorin, Gastroenterology, Bevacizumab, Oxaliplatin, Hepatic Artery, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Humans, Infusions, Intra-Arterial, Fluorouracil, Colorectal Neoplasms
Abstract

In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy.The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM.Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and10 mm, ECOG performance status 0 or 1.The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life.This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753).

Published
2022

23. Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial

Author

Marc Ychou, Michel Rivoire, Simon Thezenas, Rosine Guimbaud, Francois Ghiringhelli, Anne Mercier-Blas, Laurent Mineur, Eric Francois, Faiza Khemissa, Marion Chauvenet, Reza Kianmanesh, Marianne Fonck, Philippe Houyau, Thomas Aparicio, Marie-Pierre Galais, Franck Audemar, Eric Assenat, Evelyne Lopez-Crapez, Claire Jouffroy, Antoine Adenis, René Adam, and Olivier Bouché

Subjects
Male, Cancer Research, Liver Neoplasms, Leucovorin, Cetuximab, Middle Aged, Article, Bevacizumab, Pancreatic Neoplasms, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Camptothecin, Fluorouracil, Colorectal Neoplasms
Abstract

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48–66) with the 3-CTx versus 48.4% (95% CI: 39–57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

Published
2022

24. Paraneoplastic Cushing Syndrome in Gastrointestinal Neuroendocrine Tumour

Author

Léa Vazquez, Rania Boustany, and Laurent Mineur

Subjects
medicine.medical_specialty, Cushingoid, Case Report, Adrenocorticotropic hormone, Gastroenterology, Cushing syndrome, Neuroendocrine tumours, Internal medicine, Rare case, Paraneoplastic syndromes, medicine, RC254-282, biology, business.industry, Chromogranin A, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Neuroendocrine tumour, Oncology, biology.protein, WHO grade 1, Ketoconazole, Bilateral adrenalectomy, business, Ectopic Cushing syndrome, medicine.drug
Abstract

Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient’s prognosis and quality of life.

Published
2021

25. Sphincter‐saving surgery for ultra‐low rectal carcinoma initially indicated for abdominoperineal resection: Is it safe on a long‐term follow‐up?

Author

C. Lemanski, Denis Pezet, Philippe Rouanet, François Dravet, Eric Rullier, Marc Pocard, Jean Luc Faucheron, Sophie Gourgou, Merhdad Jafari, Laurent Mineur, Jean Michel Fabre, Jacques Balosso, Bernard Lelong, Christophe Taoum, Laurent Bresler, Michel Rivoire, Institut du Cancer de Montpellier (ICM), Centre Léon Bérard [Lyon], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU Bordeaux [Bordeaux], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut Sainte Catherine [Avignon], Service de Chirurgie d'Oncologie Digestive [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre René Gauducheau, CRLCC René Gauducheau, CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre Hospitalier Universitaire de Nancy (CHU Nancy)

Subjects
Male, [SDV]Life Sciences [q-bio], Anal Canal, law.invention, MESH: Aged, 80 and over, 0302 clinical medicine, Randomized controlled trial, intersphincteric resection, law, Prospective Studies, MESH: Aged, Aged, 80 and over, MESH: Middle Aged, Proctectomy, Abdominoperineal resection, MESH: Anal Canal, MESH: Follow-Up Studies, General Medicine, Middle Aged, Prognosis, neoadjuvant radiotherapy, Oncology, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Adult, medicine.medical_specialty, Randomization, Long term follow up, Adenocarcinoma, MESH: Prognosis, 03 medical and health sciences, Rectal carcinoma, Overall survival, medicine, Humans, ultra low rectal carcinoma, Aged, MESH: Humans, MESH: Organ Sparing Treatments, Rectal Neoplasms, business.industry, MESH: Proctectomy, MESH: Adenocarcinoma, MESH: Rectal Neoplasms, MESH: Adult, sphincter saving surgery, Intersphincteric resection, MESH: Male, MESH: Prospective Studies, Surgery, Sphincter saving surgery, business, MESH: Female, Organ Sparing Treatments, Follow-Up Studies
Abstract

International audience; Background: Rate of abdominoperineal resection (APR) varies from countries and surgeons. Surgical impact of preoperative treatment for ultra-low rectal carcinoma (ULRC) initially indicated for APR is debated. We report the 10-year oncological results from a prospective controlled trial (GRECCAR 1) which evaluate the sphincter saving surgery (SSR).Methods: ULRC indicated for APR were included (n = 207). Randomization was between high-dose radiation (HDR, 45 + 18 Gy) and radiochemotherapy (RCT, 45 Gy + 5FU infusion). Surgical decision was based on tumour volume regression at surgery. SSR technique was standardized as mucosectomy (M) or partial (PISR)/complete (CISR) intersphincteric resection.Results: Overall SSR rate was 85% (72% ISR), postoperative morbidity 27%, with no mortality. There were no significant differences between the HDR and RCT groups: 10-year overall survival (OS10) 70.1% versus 69.4%, respectively, 10.2% local recurrence (9.2%/14.5%) and 27.6% metastases (32.4%/27.7%). OS and disease-free survival were significantly longer for SSR (72.2% and 60.1%, respectively) versus APR (54.7% and 38.3%). No difference in OS10 between surgical approaches (M 78.9%, PISR 75.5%, CISR 65.5%) or tumour location (low 64.8%, ultralow 76.7%).Conclusion: GRECCAR 1 demonstrates the feasibility of safely changing an initial APR indication into an SSR procedure according to the preoperative treatment tumour response. Long-term oncologic follow-up validates this attitude.

Published
2020

26. Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author

Pierre Laurent-Puig, Laurent Mineur, Fabienne Portales, Jean-Philippe Metges, Hélène Blons, Claire Mulot, Jason E. Cain, Jean-Baptiste Bachet, Iman El Hariry, Jérôme Cros, Camille Bourreau, Pascal Hammel, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cooperator Multidisciplinary Oncology Group (GERCOR), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ERYTECH Pharma, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut Sainte Catherine [Avignon], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Gestionnaire, HAL Sorbonne Université 5, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, law.invention, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Second line, [SDV.CAN] Life Sciences [q-bio]/Cancer, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Asparaginase, Humans, In patient, predictive, Objective response, Aged, Predictive biomarker, Aged, 80 and over, circulating tumor DNA, business.industry, Middle Aged, Prognosis, medicine.disease, L-asparaginase, Progression-Free Survival, Confidence interval, Pancreatic Neoplasms, Treatment Outcome, 030104 developmental biology, phase 2, Circulating tumor DNA, 030220 oncology & carcinogenesis, Mutation, Female, Tumor Suppressor Protein p53, business, prognostic
Abstract

Purpose: Eryaspase is composed of l-asparaginase encapsulated in erythrocytes and has demonstrated significant efficacy in a randomized phase II trial. We assessed the prognostic and predictive value of circulating tumor DNA (ctDNA) in patients, plasma included in this trial. Experimental Design: Samples prospectively collected pretreatment were centrally analyzed by next-generation sequencing. Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); three groups were defined: negative ctDNA (Neg), ctDNA responders (Resp), and ctDNA nonresponders (NResp). Predictive value of ctDNA for eryaspase efficacy was investigated. Results: ctDNA was positive at baseline in 77 patients of the 113 tested patients (68%). Detectable ctDNA was an independent negative prognostic factor for OS (4.6 vs. 8.8 months; P = 0.0025) and PFS (1.6 vs. 3.3 months; P = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; P < 0.04), PFS (3.7, 3.4, 1.6 months; P < 0.0001), and OS (11.7, 6.5, 4.3 months; P < 0.0001) according to the three defined groups (Neg, Res, NResp, respectively). In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS [HR = 0.53; 95% confidence interval (CI): 0.3–0.94)] and OS (HR = 0.52; 95% CI: 0.29–0.91). Conclusions: We confirm from a prospective randomized trial that: (i) the presence of ctDNA at baseline is a major prognostic factor, (ii) the early change of ctDNA correlates with treatment outcome, and (iii) the ctDNA could be a predictive biomarker of eryaspase efficacy.

Published
2020

27. Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI)-PRODIGE 62: A multicentre, randomised, non-comparative phase II study

Author

Laetitia Dahan, Emilie Barbier, David Tougeron, Jean Philippe Metges, Samy Louafi, Christophe Borg, Roger Faroux, Lila Gaba, Christophe Louvet, Jérôme Desramé, Astrid Lièvre, Violaine Randrian, Frédéric Di Fiore, Sylvain Manfredi, Antoine Adenis, Gilles Breysacher, Pierre Laurent-Puig, Laurent Mineur, Guillaume Roquin, Anthony Lopez, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Hôpital privé Jean Mermoz, Fédération Francophone de la Cancérologie Digestive, FFCD, Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Sainte Catherine [Avignon], Hôpital Louis Pasteur [Colmar] (CH Colmar), Servier, Faculté de Médecine - Clermont-Auvergne (FM - UCA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, medicine.medical_specialty, Esophageal Neoplasms, Paclitaxel, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Esophageal cancer, Phases of clinical research, Irinotecan, 03 medical and health sciences, chemistry.chemical_compound, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Multicenter Studies as Topic, ComputingMilieux_MISCELLANEOUS, Randomized Controlled Trials as Topic, 030304 developmental biology, Cisplatin, 0303 health sciences, Chemotherapy, Hepatology, Performance status, business.industry, Gastroenterology, medicine.disease, 3. Good health, Survival Rate, chemistry, Docetaxel, 030220 oncology & carcinogenesis, Disease Progression, Quality of Life, Squamous cell cancer, Esophageal Squamous Cell Carcinoma, Fluorouracil, France, Neoplasm Recurrence, Local, business, medicine.drug
Abstract

Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but no randomised studies are available. OESIRI is a multicentre, randomised, open-label phase II trial designed to evaluate efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU versus paclitaxel as second-line therapy in patients with mESCC. The main inclusion criteria are histologically proven mESCC in progression after first-line platinum-based chemotherapy. Patients with initial resectable disease can be included if recurrence occurred within 6 months. The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. In addition, circulating tumour DNA will be monitored to assess its prognostic value.

Published
2020

28. Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial

Author

Pierre Laurent-Puig, May Mabro, Valérie Taly, Jaafar Bennouna, Claire Mulot, Julie Henriques, Olivier Bouché, Jérôme Desramé, Joëlle Egreteau, Thibault Mazard, C. Lepere, Laurent Mineur, Christophe Louvet, Dewi Vernerey, Camille Bourreau, Kariman Chaba, Aimery de Gramont, Katia Hormigos, Julien Taieb, Thierry André, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Cancer Research and Personalized Medicine - CARPEM [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint-Jacques [CHRU de Besançon], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut Sainte Catherine [Avignon], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital privé Jean-Mermoz [Lyon] (Ramsay-GDS), Institut Mutualiste de Montsouris (IMM), Hôpital Foch [Suresnes], Groupe Hospitalier Bretagne Sud (GHBS), Hôpital Robert Debré, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut hospitalier Franco-Britannique [Levallois-Perret], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), TALY, Valerie, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Treatment duration, [SDV]Life Sciences [q-bio], Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Post-hoc analysis, medicine, In patient, Stage (cooking), 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, 3. Good health, Stage III Colon Cancer, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Baseline characteristics, business, Adjuvant
Abstract

Purpose:Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.Experimental Design:ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).Results:Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.Conclusions:In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.See related commentary by Bent and Kopetz, p. 5449

Published
2021

29. Pembrolizumab with Capox Bevacizumab in patients with microsatellite stable metastatic colorectal cancer and a high immune infiltrate: The FFCD 1703-POCHI trial

Author

Romain Coriat, Nicolas Loménie, Côme Lepage, Thierry Lecomte, Violaine Randrian, Camille Kurtz, Jean-Louis Legoux, Jean-Marc Phelip, Astrid Lièvre, Pierre Laurent-Puig, Julien Taieb, Jean-François Emile, Carole Monterymard, David Tougeron, Harry Sokol, Jérémie Bez, Laurent Mineur, Claire Gallois, Laetitia Dahan, Stefano Kim, Vincent Hautefeuille, Claude Capron, Marine Gilabert, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Ambroise Paré [AP-HP], Hôpital JeanMinjoz, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Sainte Catherine [Avignon], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional d'Orléans (CHRO), CHU Amiens-Picardie, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Informatique Paris Descartes (LIPADE (URP_2517)), Université de Paris (UP), HalioDX and the 'Ligue nationale contre le cancer', Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Jonchère, Laurent, École Pratique des Hautes Études (EPHE), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Oncology, medicine.medical_specialty, Bevacizumab, Colorectal cancer, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pembrolizumab, Antibodies, Monoclonal, Humanized, DNA Mismatch Repair, 03 medical and health sciences, Antineoplastic Agents, Immunological, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Checkpoint blockade, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Humans, Medicine, Immune Checkpoint Inhibitors, Chemotherapy, Hepatology, business.industry, Tumour-infiltrating lymphocytes, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, Oxaliplatin, Clinical trial, 030220 oncology & carcinogenesis, Microsatellite Instability, 030211 gastroenterology & hepatology, Colorectal Neoplasms, business, medicine.drug
Abstract

International audience; Pembrolizumab, a PD1 immune checkpoint inhibitor (ICI), was recently reported to be very effective in patients with microsatellite instable/deficient mismatch repair metastatic colorectal cancer (MSI/dMMR mCRC), unlike patients with microsatellite stable/proficient MMR (MSS/pMMR) mCRC, in whom ICIs are generally ineffective. However, about 15% of MSS/pMMR CRCs are highly infiltrated by tumour infiltrating lymphocytes. In addition, both oxaliplatin and bevacizumab have been shown to have immunomodulatory properties that may increase the efficacy of an ICI. We formulated the hypothesis that patients with MSS/pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin and bevacizumab-based chemotherapy. POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of Pembrolizumab with Capox Bevacizumab as first-line treatment of MSS/pMMR mCRC with a high immune infiltrate for which we plan to enrol 55 patients. Primary endpoint is progression-free survival (PFS) at 10 months, which is expected greater than 50%, but a 70% rate is hoped for. Main secondary objectives are overall survival, secondary resection rate and depth of response. Patients must have been resected of their primary tumour so as to evaluate two different immune scores (Immunoscore® and TuLIS) and are eligible if one score is "high";. The first patient was included on April 20, 2021.

Published
2021

30. Clinical Relevance of Viable Circulating Tumor Cells in Patients with Metastatic Colorectal Cancer: The COLOSPOT Prospective Study

Author

Eric Assenat, Rosine Guimbaud, Jean-Pierre Daurès, Catherine Alix-Panabières, Benjamin Linot, Marc Ychou, Christelle De La Fouchardiere, Eric Francois, Stéphane Obled, Laure Cayrefourcq, Thibault Mazard, Hélène Senellart, Françoise Perriard, Laurent Mineur, Eric Terrebonne, Marianne Fonck, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre Léon Bérard [Lyon], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Sainte Catherine [Avignon], Institut Bergonié [Bordeaux], Institut de Génétique Moléculaire de Montpellier (IGMM), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, circulating tumor cells, Article, 03 medical and health sciences, 0302 clinical medicine, Circulating tumor cell, Internal medicine, medicine, Clinical significance, In patient, CellSearch® system, Prospective cohort study, EPISPOT assay, RC254-282, predictive value, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Predictive value, Peripheral blood, Measurable Disease, 030104 developmental biology, 030220 oncology & carcinogenesis, business
Abstract

Simple Summary The analysis of circulating tumor cells (CTCs) as a “real-time liquid biopsy” in epithelial tumors for personalized medicine has received tremendous attention over the past years, with important clinical implications. In metastatic colorectal cancer (mCRC), the CellSearch® system has already demonstrated its prognostic value and interest in monitoring treatment response, but the number of recovered CTCs remains low. In this article, we evaluate the early prognostic and predictive value of viable CTCs in patients with mCRC treated with FOLFIRI–bevacizumab with an alternative approach, the functional EPISPOT assay. This study shows that viable CTCs can be detected in patients with mCRC before and during FOLFIRI–bevacizumab treatment and that CTC detection at D28 and the D0–D28 CTC kinetics evaluated with the EPISPOT assay are associated with response to treatment. Abstract Background: Circulating tumor cells (CTCs) allow the real-time monitoring of tumor course and treatment response. This prospective multicenter study evaluates and compares the early predictive value of CTC enumeration with EPISPOT, a functional assay that detects only viable CTCs, and with the CellSearch® system in patients with metastatic colorectal cancer (mCRC). Methods: Treatment-naive patients with mCRC and measurable disease (RECIST criteria 1.1) received FOLFIRI–bevacizumab until progression or unacceptable toxicity. CTCs in peripheral blood were enumerated at D0, D14, D28, D42, and D56 (EPISPOT assay) and at D0 and D28 (CellSearch® system). Progression-free survival (PFS) and overall survival (OS) were assessed with the Kaplan–Meier method and log-rank test. Results: With the EPISPOT assay, at least 1 viable CTC was detected in 21% (D0), 15% (D14), 12% (D28), 10% (D42), and 12% (D56) of 155 patients. PFS and OS were shorter in patients who remained positive, with viable CTCs between D0 and D28 compared with the other patients (PFS = 7.36 vs. 9.43 months, p = 0.0161 and OS = 25.99 vs. 13.83 months, p = 0.0178). The prognostic and predictive values of ≥3 CTCs (CellSearch® system) were confirmed. Conclusions: CTC detection at D28 and the D0–D28 CTC dynamics evaluated with the EPISPOT assay were associated with outcomes and may predict response to treatment.

Published
2021

31. Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study)

Author

Isabelle Trouilloud, Nabil Baba-Hamed, Marie-Pierre Galais, David Tougeron, Romain Coriat, Jean-Philippe Metges, Olivier Bouché, Jean-Marc Phelip, Lola-Jade Palmieri, Laurent Mineur, Benoit Rousseau, Victoire Granger, Lea Saban-Roche, Pierre Michel, Julie Henriques, Jean-Marc Gornet, Emilie Soularue, Astrid Lièvre, Denis Smith, Dewi Vernery, Stéphane Obled, Gael Goujon, Christophe Locher, Anne-Laure Bignon-Bretagne, Gaetan Des Guetz, Sylvain Manfredi, Solene Doat, Bruno Buecher, Marie Dior, Carole Vitellius, Simon Pernot, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Sainte Catherine [Avignon], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre Hospitalier Universitaire [Grenoble] (CHU), Hopital Saint-Louis [AP-HP] (AP-HP), CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut Curie [Paris], Hôpital Delafontaine, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier de Meaux, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital Louis Mourier - AP-HP [Colombes], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Michallon, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, Bevacizumab, Colorectal cancer, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Growth factor receptor, Interquartile range, Internal medicine, Gastrointestinal Cancer, Antineoplastic Combined Chemotherapy Protocols, Anti‐epidermal growth factor receptor, Humans, Medicine, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Chemotherapy, Metastatic colorectal cancer, business.industry, Hazard ratio, Antibodies, Monoclonal, medicine.disease, RAS status, 3. Good health, 030220 oncology & carcinogenesis, Propensity score matching, Fluorouracil, Colorectal Neoplasms, business, medicine.drug
Abstract

Background Patients with RAS wild‐type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti‐epidermal growth factor receptor (EGFR) combined with first‐line, 5‐fluorouracil‐based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti‐EGFR. Our objective was to compare both strategies in a routine practice setting. Materials and Methods This multicenter, retrospective, propensity score–weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5‐FU‐based chemotherapy, with either delayed anti‐EGFR or immediate anti‐vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression‐free survival (PFS) and objective response rate (ORR). Results A total of 262 patients (129 in the anti‐VEGF group and 133 in the anti‐EGFR group) were included. Patients receiving an anti‐VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13–26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69–1.08, p = .2024). The delayed introduction of anti‐EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61–0.90, p = .0024). ORR was significantly higher in the anti‐EGFR group (66.7% vs. 45.6%, p = .0007). Conclusion Delayed introduction of anti‐EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti‐VEGF. Implications for Practice For RAS/RAF wild‐type metastatic colorectal cancer, patients may receive 5‐fluorouracil‐based chemotherapy plus either bevacizumab or an anti‐epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti‐EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti‐EGFR on survival, compared with the introduction of an anti‐vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti‐EGFR while waiting for RAS status., More than half of the cases of metastatic colorectal cancer harbor a RAS mutation; however, the time to obtain RAS status might be long enough to consider delayed anti‐EGFR treatment. This article reports on the two main treatment strategies for these cases.

Published
2019

32. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL)

Author

Zev A. Wainberg, David Ferry, Ravindranath Patel, Denis Pezet, Elzbieta Wojcik, Kazumasa Fujitani, Vera Gorbounova, Fernando Cabanillas, Bela Piko, Fidel David Huitzil Melendez, Agnes Ruzsa, Jean-Marc Phelip, Madhuri Bajaj, J.T. Beck, Elizabeth Won, Alexander Luft, Sara Lonardi, Peter C. Enzinger, Maen A. Hussein, Bohuslav Melichar, Daisuke Sakai, Angel Gomez Villanueva, A Madi, Georgina Garnica Jaliffe, Carlo Barone, Guillermo Mendez, Marina N. Nechaeva, György Bodoky, Hubert Ayala, Francesco Di Costanzo, Julien Taieb, David H. Ilson, Leslie Samuel, Ronald L. Burkes, Mayukh Das, Marc Van den Eynde, Charles S. Fuchs, Scott M. Berry, Ji Lin, Shuichi Hironaka, Christina Maria Gomez, Thierry Alcindor, Eric Van Cutsem, James A. Jr Reeves, Katriina Peltola, Timothy R. Asmis, Christine Brezden-Masley, Udit Verma, Javier Gallego Plazas, Isabelle Sinapi, Peter Bono, Nozomu Machida, Cynthia Coo Chua, Francisco Javier Ramirez Godinez, Annemieke Cats, Raija Kallio, Alex Beny, Hiroki Hara, Cardellino Giovanni Gerardo, Diego Lucas Kaen, Wasat Mansoor, Miguel Angel Escudero, Andràs Csilla, Akihito Tsuji, Ralf-Dieter Hofheinz, Jana Pribylova, Marianne Nordsmark, Daniel Dammrich, Maria Alejandra Bartoli, Joanna Pikiel, Robert Andrew Dichmann, Maria Di Bartolomeo, Ricardo Villalobos Valencia, Jill Lacy, Raymond Jang, Carlos Alberto Hernandez, Giuseppe Aprile, Nina A. Karaseva, Jonathan Wadsley, Ian Chau, Svetlana Protsenko, Jana Prausová, Maria Błasińska-Morawiec, Salah-Eddin Al-Batran, Hélène Senellart, Stephen Leong, Francisco Gutiérrez Delgado, Johanna C. Bendell, Laurent Mineur, M.I. Grootscholten, Hugo Ford, Russell D. Petty, Laura Visa Turmo, Roberto Carlesi, Hector Velez-Cortez, Maria Alsina, Jiri Petera, Seigo Yukisawa, Federico Longo Munoz, Mette Karen Yilmaz, Pilar Garcia Alfonso, Baruch Brenner, Irfan Firdaus, William E. Lawler, Sylvie Lorenzen, Moustapha Tehfe, Kohei Shitara, Naotoshi Sugimoto, Karen Geboes, A.J. Ten Tije, Walid Shaib, Shigenori Kadowaki, Nicolas Robert Maisey, H.M.W. Van Laarhoven, Radka Obermannova, F.L.G. Erdkamp, Rubén Dario Kowalyszyn, Joanna Wojcik-Tomaszewska, Peter Istvan Acs, Crystal S. Denlinger, Ravit Geva, Srinivasan Madhusudan, Brian Anthony DiCarlo, Ferdinando De Vita, Alejandro Molina Alavez, Gunnar Folprecht, Kensei Yamaguchi, Moses Sundar Raj, Judit Kocsis, Susanna Hegewisch-Becker, Joana Vidal Barrull, Daisuke Takahari, Tomasz Sarosiek, Luis Fein, Mohamed Hebbar, Tibor Csoszi, Manish A. Shah, Alfredo Falcone, Hugo Hool, Michel Ducreux, Per Pfeiffer, Einat Shacham-Shmueli, Howard J. Lim, Taito Esaki, Oncology, CCA - Imaging and biomarkers, CCA - Cancer Treatment and Quality of Life, and AGEM - Re-generation and cancer of the digestive system

Subjects
Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Esophageal Neoplasms, Adenocarcinoma, Antibodies, Monoclonal, Humanized, Placebo, Sudden death, Gastroenterology, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, Internal medicine, medicine, Clinical endpoint, Humans, Progression-free survival, Aged, Intention-to-treat analysis, Performance status, business.industry, Hazard ratio, Middle Aged, Vascular Endothelial Growth Factor Receptor-2, Progression-Free Survival, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Female, Esophagogastric Junction, Fluorouracil, Cisplatin, business
Abstract

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

Published
2019

33. Contact x-ray brachytherapy (Papillon) in addition to chemoradiotherapy to improve organ preservation in early cT2-T3 rectal adenocarcinoma: The 3-year results of OPERA randomized trial (NCT02505750)

Author

Jean-Pierre Gerard, Nicolas N. Barbet, Tanguy Pacé-Loscos, Nicolas Magné, Jessica Serrand, Laurent Mineur, Melanie Deberne, Thomas Zilli, Amandeep Singh Dhadda, and Arthur Sun Myint

Subjects
Cancer Research, Oncology
Abstract

3512 Background: The OPERA trial was testing the hypothesis that Contact x-ray brachytherapy (CXB) 50 kV boost will increase the rectal preservation rate in early T2-T3ab rectal adenocarcinoma. We present the 3 years clinical results. Methods: Inclusion criteria were: Age > 18 years, PS: 0-1, adenocarcinoma, distal - middle rectum, cT2-T3ab cN0-N1 < 8mm staged using MRI, M0. Stratification: T < vs ≥ 3 cm diameter. Control arm (A) was chemoradiotherapy (CRT) 45Gy/ 5 weeks with concurrent chemotherapy (Capecitabine 825 mg / m2) and external beam radiotherapy boost (9Gy/ 5 fr/ 1 week). Experimental arm used the same CRT (Cape 45) but the boost used CXB (90 Gy/ 3 fr/ 4 weeks). CXB was given first (B1) for tumor < 3 cm and after cap 45 (B2) for tumor ≥ 3 cm. Response assessment was made at week 14 after treatment start using palpation, endoscopy and MRI. A new assessment could be made at week 20 and 24 with a second MRI.TME was recommended in case of Partial response, Watch& Wait in case of clinical complete response (cCR). Bowel function measurement used LARS score. Main end- point was: Rate of organ preservation at 3 years. The hypothesis (in 2014) was 20% arm A vs 40% arm B (HR:0.53). Results: Between 5-2015 and 6-2020, 144 patients were included (France 96, UK 44, Switzerland 4). The analysis was made in 01-2022 with a median Follow-up time of 34 months. Treatment compliance was good in ≥ 90% of patients. Table gives main patients characteristics and clinical outcome. At three years the OP rate (Kaplan Meier estimate) was respectively arm A vs B: 60% vs 81% (HR 0.34 [95% CI 0.19 – 0.73]; p= 0.005). At three years OP for group A1 and B1 were: 65% vs 97% (HR 0.081 [95% CI 0.01-0.64]; p= 0.02). Conclusions: A CXB boost, when combined with chemoradiotherapy, increases the rate of organ preservation in early rectal adenocarcinoma. Starting with CXB in T < 3 cm appears as an attractive option. A B A1 (T < 3cm) B1 (T < 3cm) N° patient 71 73 30 32 Median age 68 69 69 70 Gender M/F 45/26 43/30 18/12 18/14 T2/T3 45/26 47/26 25/5 29/3 Distal/middle 53/18 53/20 21/9 27/5 cCR (W 14-24) 61% 90% p < 0.001 70% 94% p = 0.027 TME 26 12 8 1 Death 2 2 1 0 LARS < 30 80% 83% 87% 86%.

Published
2022

34. The Activity of Crizotinib in Chemo-Refractory MET-Amplified Esophageal and Gastric Adenocarcinomas: Results from the AcSé-Crizotinib Program

Author

Rosine Guimbaud, Carlos Gomez-Roca, Laurent Mineur, Thomas Aparicio, Emmanuelle Samalin, Gilles Vassal, Jannick Selves, Christelle De La Fouchardiere, Paul Arthur Haineaux, Yves Menu, Florence Mary, Alain Gratet, Nathalie Cozic, N. Colignon, Jérôme Edouard Plaza, Laetitia Johnson, Frédéric Legrand, Emeline Meriaux, Thierry Lecomte, Gestionnaire, Hal Sorbonne Université, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut du Cancer de Montpellier (ICM), Hôpital Avicenne [AP-HP], Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Clinique Pasteur [Toulouse], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut national du cancer [Boulogne] (INCA), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Adult, Cancer Research, medicine.medical_specialty, Esophageal Neoplasms, [SDV]Life Sciences [q-bio], Met amplification, Adenocarcinoma, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Refractory, Crizotinib, Stomach Neoplasms, Internal medicine, medicine, Humans, Pharmacology (medical), In patient, Prospective Studies, Original Research Article, Protein Kinase Inhibitors, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, Tolerability, 030220 oncology & carcinogenesis, Immunohistochemistry, business, Fluorescence in situ hybridization, medicine.drug
Abstract

Background The AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric MET-amplified adenocarcinomas. Objective The objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric MET-amplified adenocarcinoma who have no alternative treatment options. Patients and Methods MET expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6 MET copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib. Results MET was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5–70), the best overall response rate was 55.6% (95% CI 21.2–86.3), with median progression-free survival of 3.2 months (95% CI 1.0–5.4), and overall survival of 8.1 months (95% CI 1.7–24.6). Safety was consistent with that previously reported for crizotinib. Conclusions Large-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation. Trial Registration Number NCT02034981. Date of Registration 14 January 2014.

Published
2021

35. Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first‐line treatment in patients with metastatic pancreatic adenocarcinoma ( GATE 1)

Author

Caroline Mollevi, Marc Ychou, Hélène de Forges, Fabienne Portales, Thomas Walter, Catherine Lombard-Bohas, Laurent Mineur, Emmanuelle Samalin, Thibaut Mazard, Eric Assenat, Marie Dupuy, Evelyne Lopez-Crapez, Alexandre Ho-Pun-Cheung, Florence Boissière-Michot, Institut du Cancer de Montpellier (ICM), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Sainte Catherine [Avignon], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), and Michel-Avella, Amandine

Subjects
Male, Oncology, Cancer Research, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], efficacy, pancreatic cancer, Phases of clinical research, medicine.disease_cause, Deoxycytidine, MESH: ErbB Receptors, combination therapy, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, MESH: Erlotinib Hydrochloride, MESH: Trastuzumab, Neoplasm Metastasis, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, Cetuximab, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, ErbB Receptors, Gene Expression Regulation, Neoplastic, MESH: Receptor, ErbB-2, [SDV] Life Sciences [q-bio], MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: Survival Analysis, Female, KRAS, Erlotinib, MESH: Pancreatic Neoplasms, medicine.drug, Adult, medicine.medical_specialty, Combination therapy, Erlotinib Hydrochloride, 03 medical and health sciences, Pancreatic cancer, Internal medicine, medicine, Humans, Aged, MESH: Humans, business.industry, MESH: Deoxycytidine, MESH: Adult, medicine.disease, Survival Analysis, Gemcitabine, MESH: Neoplasm Metastasis, MESH: Male, Pancreatic Neoplasms, business, MESH: Female
Abstract

International audience; In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed.

Published
2021

36. Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a

Author

Julien, Taieb, Valérie, Taly, Julie, Henriques, Camille, Bourreau, Laurent, Mineur, Jaafar, Bennouna, Jérôme, Desrame, Christophe, Louvet, Céline, Lepere, May, Mabro, Joëlle, Egreteau, Olivier, Bouche, Claire, Mulot, Katia, Hormigos, Kariman, Chaba, Thibault, Mazard, Aimery, de Gramont, Dewi, Vernerey, Thierry, André, and Pierre, Laurent-Puig

Subjects
Male, Duration of Therapy, Chemotherapy, Adjuvant, Colonic Neoplasms, Humans, Female, Prospective Studies, Prognosis, Disease-Free Survival, Article, Aged, Circulating Tumor DNA, Neoplasm Staging
Abstract

Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.ctDNA was tested forOf 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.

Published
2021

37. Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19)

Author

Astrid Lièvre, Anthony Turpin, Isabelle Ray-Coquard, Karine Le Malicot, Juliette Thariat, Guido Ahle, Cindy Neuzillet, Xavier Paoletti, Olivier Bouché, Kais Aldabbagh, Pierre Michel, Didier Debieuvre, Anthony Canellas, Marie Wislez, Lucie Laurent, May Mabro, Raphael Colle, Anne-Claire Hardy-Bessard, Laura Mansi, Emeline Colomba, Jean Bourhis, Philippe Gorphe, Yoann Pointreau, Ahmed Idbaih, Renata Ursu, Anna Luisa Di Stefano, Gérard Zalcman, Thomas Aparicio, Solenne Moulin, Olivier Leleu, Sylvie Leparree, Henri Goasdoue, Christine Piprot, Gerald Tourneur, Vincent Bayart, Delphine Lignier, Emma Lachaier, Marwa Khamari, Alexandre Coutte, Nicolas Siembida, Aline Houessinon, Jean Marc Regimbeau, Bruno Chauffert, Aurélie Moreira, Vincent Hautefeuille, Christine Hee, Mathieu Boone, Céline Bihan, Emilie Chive, Stéphane Poulet-Potriquier, Rachida Fahem, Dominique Luet, Guillaume Roquin, Carole Vitellius, Nathanaëlle Cornet-Trichereau, François-Xavier Caroli-Bosc, Anne Thirot-Bidault, Stanislas Ropert, Julie Gachet - Masson, Mélanie Dehais, Gwen-Ael L'helgoualc'h, Ibrahim Ali-Mahamadou, Safia Talfi, Laure Belmont, Dieudonné Kilendo, Nasro Benrezzak, Emeline Dubief, Guillaume Conroy, Laurence Delique, Maud Basso, Isabelle Pons, Karine Salignon, Anne-Laure Villing, Emmanuelle Mougenot, Cassandra Porebski, Asma Guiatni, Nicolas Cloarec, Laurent Mineur, Marie Bouchaud, Céleste David, Annie Peytier, Thomas Greletty, Franck Audemar, Emanuelle Vignes, Floriane Minne, Guillaume Goldzak, Fabienne Huysman, Fayçal Hocine, Zaher Lakkis, Guillaume Meynard, Hamadi Almotlak, Elodie Klajer, Xu-Shan Sun, Julie Wasselin, Pascale Catala, Claire Mazuy, Hélène Vandamme, Jean-Briac Prevost, Aurélie Fadin, Laurent Basson, Jean-Baptiste Huguet, Emmanuelle Dos Santos, Bérangère Jany, Alain Saad, Frédéric Goutorbe, Eric Oziol, Mohamed Ramdani, Ouafae Kadiri, Delphine Garbay, Clotilde Huet, Etienne Giroux Leprieur, Wen Teng, Justine Monvoisin, Patrick Arnaud Coffin, Sylvie Roux, Hubert Orfeuvre, Mélanie Chagros, Didier Pillon, Agathe Rassoul, Pierre Guillaume Poureau, Cécile Novello, François Ducray, Cécile Trouba, Vianney Bastit, Emmanuel Babin, Vincent Leon, Anne-Catherine Courtecuisse, Julie Vambre, Vincent Tack, Christophe Desauw, Fatima Meniai, Christina Peres, Aurélie Esparcieux, Hervé Perrier, Nathalie Doux, Régis Kaphan, Bertrand Roques, Christine Rebischung, Dominique Mille, Gaëlle Fernandes, Naceur Abdelli, Natacha Jousset, Pierre Combe, Eric Jonveaux, Patrick Dumont, Marc Kanaan, Corinne Berthelot Gras, Valérie Panis, Laure Kaluzinski, Marjolène Venant-Valery, You-Heng Lam, Laura Vallee, Frédéric Riviere, Muriel Durand, Dihya Benghadid, Emilie Villeneuve, Olivia Hentic Dhome, Zedjiga Bounouar, Louis De Mestier, Jacqueline Dubois, Magali Eyriey, Lionel Moreau, Dib Baihas, Kaïs Aldabbagh, Dominique Degriffolet, Virginie Sebbagh, Jean-Christophe Seghezzi, Marion Lozach-Brugirard, Julie Mandrou, Loubna Mavier, Florence Hennetier, Jean-Philippe Wagner, Elisabeth Carola, Karthiga Chandirakumaran, Sandrine Loutski, Isabelle Cojean-Zelek, Amina Bouras, Sandrine Lacour, Fahem Froura, Hadjer Ben Nadji, Sophie Cattelain, Franck Darloy, Geneviève Jolimoy Boilleau, Cyrielle Maissiat, Ariane Darut-Jouve, Véronique Lorgis, Ikram Charifi-Alaoui, François Ghiringhelli, Antoine Drouillard, Marie Chaix, Sylvain Manfredi, Côme Lepage, Alice Gagnaire, Marianne Latournerie, Sofia jourdan, Nora Perrot, Mireille folia, Anne Minello, Jean-Louis Jouve, Marielle Fery, Alain Landau, Diane Evrard, Bruno Valenza, Jean-François Paitel, Laetitia Chablais, Thomas Kreitmann, Laurence Lancry-Lecomte, Adrien Monard, Eve Faugeras, Paul Boucheret, Cécile Glommeau, Christine Tchikladze, Claire Garnier Tixidre, Jérôme Long, Manel Zaidi, Véronique Delabarre, Juliette Meyzenc, Loïc Ferrand, Denis Moro-Sibilot, Paul Bouheret, Cécile Leyronnas, Camille Herve, Audrey Thoor, Emanuelle Jacquet, Gaël Roth, Videsheka Madapathage-Senanyake, Peggy Chupeau, Elsa Bieber, Maud Rosso, Isabelle Lepage, Frank Priou, Margot Laly, Sylvie Aprelon, Natacha Sobolak, Helen Homokos, Fabienne Watelle, Alice Pham-Becker, Géraldine Lauridant, Charlotte Dujardin, Etienne Lenglin, Aimée Nienguet Tsota, Sophie Dominguez, Alexandra Forestier, Franck Nouvel, Justine Lerooy, Céline Ratajczak, Olivier Romano, Dorothéee Brzyski, Aurélien Barriere, Dominique Genet, Julien Tisse, Xavier Zasadny, Adeline Grelet, Amélie Hennion-Imbault, Eglantine Haustraete, Samy Louafi, Manal Awad, Younes Zekri, Caroline Cheneau, Nolwen Leissen, Joëlle Egreteau, Alexandra Breant, Matthieu Sarabi, Stéphanie Labonne, Julien Forestier, Céline Leclercq, Florence Prunier-Bossion, Isabelle Ray Coquard, Marielle Guillet, Aurélie Theillaumas, Emilie Prome, Thomas Walter, Pierre Philouze, Melody Lawo, Solène De Talhouet, Johanne Beuvelot, Yann Molin, Marie Bellecoste Martin, Maud Saussereau, Lauren Agnelli, Nicolas Fakhry, Christophe Laplace, Emmanuelle Norguet Monnereau, Céline Boucard, Kahina Djenad, Catherine Fontaine, Jean-François Seitz, Laétitia Dahan, Julie Sigrand, Muriel Duluc, Christophe Locher, Marjory Fleury, Ange Brou Marie, Ramdane Berkane, Séverine Poupblanc, Dominique Auby, Daniela Petran, Patrick Texereau, Elodie Guerineau, Morgan Andre, Linda Mahjoubi, Fanny Sarrazin, Sonia Jeanson, Anthony Gschwend, Virginie Birr, Mathieu Fore, Monique Noirclerc, Sihem Dahou, Dominique Spaeth, Mélanie Lambotin, Thomas Lelu, Benjamin Linot, Nathalie Hugon, Dominique Rousseau, Hélène Castanie, Carole Lenne, Alain Lortholary, Anatole Cessot, Messaouda Merzoug, Cécile Naudin, Jean-Michel Vannetzel, Ghina Aziz, Yacine Hadj Arab, Stéphanie Pernes, Isabelle Roche-Lachaise, Frédéric Fiteni, Hadjer Yahiaoui, Gwendoline Marel Lopez, Jeanne Oddoz, Fabienne Peira, Olivier Michel, Jérôme Meunier, Brahim Ouahrani, Antoine Roger, Sonia Branco, Van Nguyen, Mathilde Gisselbrecht, Ghania Hammad, Pierre Mordant, Magda Stroksztejn, Marc Pocard, Luc Nlo Meyengue, Emmanuelle Sacco, Sophie Simon Anne, Elizabeth Fabre-Guillevin, Marine Slim, Aziz Zaanan, Jacques Cadranel, Johan Pluvy, Rénata Ursu, Amyrath Geraldo, Rime Lihi, Maryline Vo, Zohra Brouk, Raphaël Colle, Mostefa Bennamoun, Fabrice Lacan, Christophe Louvet, Soraya Mebarki, Marianne Veyri, Elena Paillaud, Christelle Lucas, Olivier Dubreuil, Jamila Lyamani, Hanane Agguini, Emilie Soularue, Clément Jourdaine, Benjamin Verillaud, Hakima Herzine, Eric Raymond, Nathalie Mathiot, Lola Jade Palmieri, Christian Epanya, Julien Taieb, Eliane Bertrand, Gaël Goujon, Céline Namour, Benoit Gazeau, Biljana Zafirova, Haitham Mirghani, Catherine Belin, Kahina Belkhir, Myriam Gharib, Aurore Vozy, Karim Amrane, Jean-Philippe Spano, Johanna Wassermann, Loic Feuvret, Jean-Baptiste Bachet, Sara Philonenko, Laetitia Guillot, Marion Zabbe, Stéphanie Gibiat, Camille Baylot, Aude Jouinot, Nicolas Leduc, Sabine Vieillot, Laurie James, Camille Ducerf, Jean-Frédéric Blanc, Claire Falandry Leger, Virginie Wautot, Marion Chauvenet, Aude Vincent, David Tougeron, Sandrine Goulvent, Etienne Suc, Anne-Pascale Laurenty, Eric Marquis, Margaux Bonnaire, Maxime Dewolf, Esteban Brenet, Delphine Billard, Claude-Fabien Litre, Antoine Dumazet, Damien Botsen, Marion Vazel, Claire Carlier, David Bonnerave, Charles Marchand-Crety, Olivier Bouche, Patricia Fosse, David Sefrioui, Sarah Watson, Fatah Torche, Thierry Muron, Stéphane Natur, Romain Desgrippes, Véronique Bihel, François-Régis Ferrand, Caroline Leiterer, Julie Lavole, Claire Moquet, Nathalie Pressoir, Catherine Dziukala, Catherine Ligeza Poisson, Abdelhalim Naji, Nicolas Williet, Jean-Marc Phelip, Fabrice Di Palma, Amina Kherrour Mehdi, Julien Langrand-Escure, Pierre Fournel, Grégoire Pigne, Léa Saban-Roche, Nicolas Magne, Cécile Vassal, Jean-Philippe Jacquin, Carole Ramirez, Alexis Vallard, Olivier Collard, Romain Rivoirard, Ivan Graber, Stéphanie Trager Maury, Elodie Duboisset, Jorge Ayllon Ugarte, Dalilia Rami, Christine Saler, Manon Reinbolt, Clara Le Fevre, Meher Ben Abdelghani, Louis-Marie Dourthe, Joffrey Perruisseau-Carrier, Marlène Nguimpi-Tambou, Flavie Barret, Luisa Di Stefano Anna, Annie Balthazard, Camille Vassord-Dang, Mathilde Le Marchand, Julien Vergniol, Iulia Pripon, Axelle Daemaegdt, Vanessa Latry, Muna Larrieu, Gaëlle Landry, Laetitia Touihri Maximin, Francesco Del Piano, Agnès Barlet, Mylène Vernisse, Sophie Lafond, Charline Genin, Camille Sibertin-Blanc, Emilien Chabrillac, Caroline Gregoire, Sébastien Vergez, Quentin Panouille, Rosine Guimbaud, Floriane Richa, Loïc Lebellec, Sophie Gounin, Guillaume Buiret, Marine Baudin, Hervé Hamon, Anne-Claire Deshorgue, Eduardo Barrascout, Stéphanie Legrand, Morgane Houlze, Linda Cambula, Anthony Lopez, Guillaume Fouquet, Kahina Touabi, Adeline GermaIn, Benoit Godbert, Florence Voivret, Julie Perrin, Rosa Da Silva, Emilie Bernichon, GCO-002 CACOVID-19 collaborators/investigators, Moulin, S., Leleu, O., Leparree, S., Goasdoue, H., Piprot, C., Tourneur, G., Bayart, V., Lignier, D., Lachaier, E., Khamari, M., Coutte, A., Siembida, N., Houessinon, A., Regimbeau, J.M., Chauffert, B., Moreira, A., Hautefeuille, V., Hee, C., Boone, M., Bihan, C., Chive, E., Poulet-Potriquier, S., Fahem, R., Luet, D., Roquin, G., Vitellius, C., Cornet-Trichereau, N., Caroli-Bosc, F.X., Thirot-Bidault, A., Ropert, S., Gachet-Masson, J., Dehais, M., L'helgoualc'h, G.A., Ali-Mahamadou, I., Talfi, S., Belmont, L., Kilendo, D., Benrezzak, N., Dubief, E., Conroy, G., Delique, L., Basso, M., Pons, I., Salignon, K., Villing, A.L., Mougenot, E., Porebski, C., Guiatni, A., Cloarec, N., Mineur, L., Bouchaud, M., David, C., Peytier, A., Greletty, T., Audemar, F., Vignes, E., Minne, F., Goldzak, G., Huysman, F., Hocine, F., Lakkis, Z., Mansi, L., Meynard, G., Almotlak, H., Klajer, E., Sun, X.S., Wasselin, J., Catala, P., Mazuy, C., Vandamme, H., Prevost, J.B., Fadin, A., Basson, L., Huguet, J.B., Dos Santos, E., Jany, B., Saad, A., Goutorbe, F., Oziol, E., Ramdani, M., Kadiri, O., Garbay, D., Huet, C., Giroux Leprieur, E., Teng, W., Monvoisin, J., Arnaud Coffin, P., Roux, S., Orfeuvre, H., Chagros, M., Pillon, D., Rassoul, A., Poureau, P.G., Novello, C., Ducray, F., Trouba, C., Bastit, V., Babin, E., Thariat, J., Leon, V., Courtecuisse, A.C., Vambre, J., Tack, V., Desauw, C., Meniai, F., Peres, C., Esparcieux, A., Perrier, H., Doux, N., Kaphan, R., Roques, B., Rebischung, C., Mille, D., Fernandes, G., Abdelli, N., Jousset, N., Combe, P., Jonveaux, E., Dumont, P., Kanaan, M., Berthelot Gras, C., Panis, V., Kaluzinski, L., Venant-Valery, M., Lam, Y.H., Vallee, L., Riviere, F., Durand, M., Benghadid, D., Villeneuve, E., Hentic Dhome, O., Laurent, L., Bounouar, Z., De Mestier, L., Dubois, J., Eyriey, M., Moreau, L., Ahle, G., Baihas, D., Aldabbagh, K., Degriffolet, D., Sebbagh, V., Seghezzi, J.C., Lozach-Brugirard, M., Mandrou, J., Mavier, L., Hennetier, F., Wagner, J.P., Carola, E., Chandirakumaran, K., Loutski, S., Cojean-Zelek, I., Bouras, A., Lacour, S., Froura, F., Ben Nadji, H., Cattelain, S., Darloy, F., Jolimoy Boilleau, G., Maissiat, C., Darut-Jouve, A., Lorgis, V., Charifi-Alaoui, I., Ghiringhelli, F., Drouillard, A., Chaix, M., Manfredi, S., Lepage, C., Gagnaire, A., Latournerie, M., Jourdan, S., Perrot, N., Folia, M., Minello, A., Jouve, J.L., Fery, M., Landau, A., Evrard, D., Valenza, B., Paitel, J.F., Chablais, L., Kreitmann, T., Lancry-Lecomte, L., Monard, A., Faugeras, E., Boucheret, P., Glommeau, C., Tchikladze, C., Garnier Tixidre, C., Long, J., Zaidi, M., Delabarre, V., Meyzenc, J., Ferrand, L., Moro-Sibilot, D., Bouheret, P., Leyronnas, C., Herve, C., Thoor, A., Jacquet, E., Roth, G., Madapathage-Senanyake, V., Chupeau, P., Bieber, E., Rosso, M., Lepage, I., Priou, F., Laly, M., Aprelon, S., Sobolak, N., Homokos, H., Pointreau, Y., Watelle, F., Pham-Becker, A., Lauridant, G., Turpin, A., Dujardin, C., Lenglin, E., Nienguet Tsota, A., Dominguez, S., Forestier, A., Nouvel, F., Lerooy, J., Ratajczak, C., Romano, O., Brzyski, D., Barriere, A., Genet, D., Tisse, J., Zasadny, X., Grelet, A., Hennion-Imbault, A., Haustraete, E., Louafi, S., Awad, M., Zekri, Y., Cheneau, C., Leissen, N., Egreteau, J., Breant, A., Sarabi, M., Labonne, S., Forestier, J., Leclercq, C., Prunier-Bossion, F., Ray Coquard, I., Guillet, M., Theillaumas, A., Prome, E., Walter, T., Philouze, P., Lawo, M., De Talhouet, S., Beuvelot, J., Molin, Y., Bellecoste Martin, M., Saussereau, M., Agnelli, L., Fakhry, N., Laplace, C., Norguet Monnereau, E., Boucard, C., Djenad, K., Fontaine, C., Seitz, J.F., Dahan, L., Sigrand, J., Duluc, M., Locher, C., Fleury, M., Brou Marie, A., Berkane, R., Poupblanc, S., Auby, D., Petran, D., Texereau, P., Guerineau, E., Andre, M., Mahjoubi, L., Sarrazin, F., Jeanson, S., Gschwend, A., Birr, V., Debieuvre, D., Fore, M., Noirclerc, M., Dahou, S., Spaeth, D., Lambotin, M., Lelu, T., Linot, B., Hugon, N., Rousseau, D., Castanie, H., Lenne, C., Lortholary, A., Cessot, A., Merzoug, M., Naudin, C., Vannetzel, J.M., Aziz, G., Hadj Arab, Y., Pernes, S., Roche-Lachaise, I., Fiteni, F., Yahiaoui, H., Marel Lopez, G., Oddoz, J., Peira, F., Michel, O., Meunier, J., Ouahrani, B., Roger, A., Branco, S., Nguyen, V., Gisselbrecht, M., Hammad, G., Mordant, P., Stroksztejn, M., Pocard, M., Nlo Meyengue, L., Aparicio, T., Sacco, E., Simon Anne, S., Fabre-Guillevin, E., Wislez, M., Slim, M., Zaanan, A., Cadranel, J., Pluvy, J., Ursu, R., Geraldo, A., Lihi, R., Vo, M., Brouk, Z., Colle, R., Bennamoun, M., Lacan, F., Louvet, C., Mebarki, S., Veyri, M., Paillaud, E., Lucas, C., Dubreuil, O., Lyamani, J., Idbaih, A., Agguini, H., Soularue, E., Canellas, A., Zalcman, G., Jourdaine, C., Verillaud, B., Herzine, H., Raymond, E., Mathiot, N., Palmieri, L.J., Epanya, C., Taieb, J., Bertrand, E., Goujon, G., Namour, C., Gazeau, B., Zafirova, B., Mirghani, H., Belin, C., Belkhir, K., Gharib, M., Vozy, A., Amrane, K., Spano, J.P., Wassermann, J., Feuvret, L., Bachet, J.B., Philonenko, S., Guillot, L., Zabbe, M., Gibiat, S., Baylot, C., Jouinot, A., Leduc, N., Vieillot, S., James, L., Ducerf, C., Blanc, J.F., Falandry Leger, C., Wautot, V., Chauvenet, M., Vincent, A., Tougeron, D., Goulvent, S., Suc, E., Laurenty, A.P., Marquis, E., Bonnaire, M., Dewolf, M., Brenet, E., Billard, D., Litre, C.F., Dumazet, A., Botsen, D., Vazel, M., Carlier, C., Bonnerave, D., Marchand-Crety, C., Bouche, O., Fosse, P., Sefrioui, D., Michel, P., Watson, S., Neuzillet, C., Torche, F., Muron, T., Natur, S., Desgrippes, R., Bihel, V., Ferrand, F.R., Leiterer, C., Lavole, J., Moquet, C., Pressoir, N., Dziukala, C., Ligeza Poisson, C., Naji, A., Williet, N., Phelip, J.M., Di Palma, F., Kherrour Mehdi, A., Langrand-Escure, J., Fournel, P., Pigne, G., Saban-Roche, L., Magne, N., Vassal, C., Jacquin, J.P., Ramirez, C., Vallard, A., Collard, O., Rivoirard, R., Graber, I., Trager Maury, S., Duboisset, E., Ayllon Ugarte, J., Rami, D., Saler, C., Reinbolt, M., Le Fevre, C., Ben Abdelghani, M., Dourthe, L.M., Perruisseau-Carrier, J., Nguimpi-Tambou, M., Barret, F., Di Stefano Anna, L., Balthazard, A., Mabro, M., Vassord-Dang, C., Le Marchand, M., Vergniol, J., Pripon, I., Daemaegdt, A., Latry, V., Larrieu, M., Landry, G., Touihri Maximin, L., Del Piano, F., Barlet, A., Vernisse, M., Lafond, S., Genin, C., Sibertin-Blanc, C., Chabrillac, E., Gregoire, C., Vergez, S., Panouille, Q., Guimbaud, R., Richa, F., Lebellec, L., Gounin, S., Buiret, G., Baudin, M., Hamon, H., Deshorgue, A.C., Barrascout, E., Legrand, S., Houlze, M., Cambula, L., Lopez, A., Fouquet, G., Touabi, K., GermaIn, A., Godbert, B., Voivret, F., Perrin, J., Da Silva, R., Bernichon, E., Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CH Colmar, Institut Curie [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Beaujon, Hôpital Foch [Suresnes], CHU Saint-Antoine [AP-HP], ARCAGY-GINECO, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), Département de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Département de médecine oncologique [Gustave Roussy], Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), Centre Jean Bernard [Institut Inter-régional de Cancérologie - Le Mans], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), AbbVie, Merck, Carthera, Transgene, Nutritheragene, Roche, Air Liquide, Eli Lilly Japan, LEO Pharma Research Foundation, Bayer, Novartis, Sanofi, Biogen, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Cancer Research, medicine.medical_treatment, Disease, law.invention, Cohort Studies, 0302 clinical medicine, Mechanical ventilation, Risk Factors, law, Neoplasms, Medicine, Prospective Studies, Prospective cohort study, Original Research, Cancer, Intensive care unit, 3. Good health, Death, Oncology, 030220 oncology & carcinogenesis, Female, France, Immunotherapy, Cohort study, medicine.medical_specialty, chemotherapy. radiotherapy, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, Humans, Chemotherapy, Mortality, Pandemics, Aged, Retrospective Studies, Radiotherapy, SARS-CoV-2, business.industry, COVID-19, Retrospective cohort study, Odds ratio, medicine.disease, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, COVID-19/mortality, France/epidemiology, Neoplasms/mortality, Neoplasms/therapy, Neoplasms/virology, SARS-CoV-2/isolation & purification, 030104 developmental biology, business
Abstract

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Published
2020

38. PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer

Author

A. Abakar Mahamat, N. Mathé, Roger Faroux, R. Boustany, P. Soulié, L. Moreau, Isabelle Baumgaertner, R. Hervé, J. M. Phelip, D. Smith, J. M. Bons, L. Vazquez, Laurent Miglianico, Eric Francois, Rosine Guimbaud, Laurent Mineur, Louis-Marie Dourthe, A. L. Villing, S. Remy, E. Achille, N. Bonichon, Carine Plassot, and I. Rabbia

Subjects
0301 basic medicine, Oncology, Male, Colorectal cancer, Cancer Treatment, ECOG Performance Status, Cetuximab, medicine.disease_cause, Toxicology, Pathology and Laboratory Medicine, Metastasis, 0302 clinical medicine, Antineoplastic Agents, Immunological, Basic Cancer Research, Medicine and Health Sciences, Neoplasm Metastasis, Paronychia, Aged, 80 and over, Univariate analysis, Multidisciplinary, Hazard ratio, Smoking, Middle Aged, Tumor Resection, Primary tumor, Surgical Oncology, Treatment Outcome, 030220 oncology & carcinogenesis, Medicine, Female, KRAS, Colorectal Neoplasms, medicine.drug, Research Article, Compliance, Clinical Oncology, Adult, medicine.medical_specialty, Science, Surgical and Invasive Medical Procedures, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Malignant Tumors, Internal medicine, medicine, Humans, neoplasms, Aged, Colorectal Cancer, Folliculitis, Toxicity, Surgical Resection, business.industry, Proportional hazards model, Cancers and Neoplasms, Biology and Life Sciences, medicine.disease, digestive system diseases, 030104 developmental biology, Clinical Medicine, business
Abstract

Background Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. Patients and methods PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. Results A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6–12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. Conclusions ECOG PS

Published
2020

39. 337 Pembrolizumab in combination with xelox bevacizumab in patients with microsatellite stable (MSS) metastatic colorectal cancer and a high immune infiltrate: a proof of concept study. FFCD 1703 POCHI

Author

Julien Taieb, Jean-François Emile, Claude Capron, David Tougeron, Romain Coriat, Stephano Kim, Jean-Marc Phelip, Laetitia Dahan, Violaine Randrian, Jean Louis Legoux, Marine Gilabert, Vincent Hautefeuille, Claire Gallois, Pierre Laurent-Puig, Laurent Mineur, Harry Sokol, Bez Jérémie, Carole Monterymard, Côme Lepage, Thierry Lecomte, and Astrid Lièvre

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Bevacizumab, business.industry, Colorectal cancer, Tumor-infiltrating lymphocytes, Pembrolizumab, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Primary tumor, lcsh:RC254-282, Oxaliplatin, Capecitabine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, FOLFOX, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, medicine.drug
Abstract

Background Immune checkpoint inhibitors (ICI) are very effective in deficient DNA mismatch-repair system (dMMR)/microsatellite instable (MSI) metastatic colorectal cancer (mCRC). About 15% of MSS/pMMR CRCs are highly infiltrated by tumor infiltrating lymphocyte (TIL) with a good prognosis. Some immune scores based on CD3+ and/or CD8+ T-cells infiltration are validated and reproducible, especially TuLIS1 and Immunoscore®.2 No data are available concerning efficacy of ICI in this subpopulation of mCRC. Pembrolizumab, an anti-PD1 (programmed death-1) monoclonal antibody has been recently reported very effective in patients with MSI/dMMR mCRC. Immunogenic cell death induced by chemotherapy, such as oxaliplatin, could increase the efficacy of ICI. We formulated the hypothesis that patients with a pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin-based chemotherapy. Methods POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of pembrolizumab in combination with chemotherapy as first-line treatment of pMMR mCRC with a high immune infiltrate. Primary objective is PFS at 10 months, i.e. number of patients alive and without radiological and/or clinical progression at 10 months evaluated by the investigator. Main secondary objectives are overall survival, secondary resection rate, depth of response and early tumour shrinkage. Main inclusion criteria are pMMR mCRC untreated for metastatic disease and with at least one measurable metastatic target according to RECIST v1.1 criteria. Patients must have resected primary tumor to evaluate two different immune scores (Immunoscore® and TuLIS) and patients are eligible if one score is ‘high’. Patients will receive combination of pembrolizumab (200 mg), bevacizumab (7.5 mg/kg), oxaliplatin (130 mg/m²) and capecitabine (2000 mg/m²/day, on day 1 to 14). Treatment will be repeated every 3 weeks until disease progression or unacceptable toxicity. The clinical hypotheses are to increase PFS at 10 months from 50% to 70%. With a one-sided type error of 5%, power of 85%, 10% rate of patients lost to follow-up or not evaluable, 55 patients have to be included. If 32 patients or more are alive and without progression at 10 months, the treatment will be considered as effective. Thus, with 15% ‘high’ immune score, about 400 patients must be tested in order to include 55 patients in POCHI trial. The ancillary study will consist to identify predictive biomarkers of response and included expression of PD-L1, circulating lymphocytes circulating tumour DNA, mutational load and gut microbiota. Inclusions will start in September 2020 and theoretical end of recruitment is 2023. Results N/A Conclusions N/A Acknowledgements We thank all the cooperative groups (FFCD – UNICANCER GI– GERCOR) for their contribution and participation to the present trial. We thank MSD and HalioDX for their support. Trial Registration NCT04262687 Ethics Approval This study was approved by ‘Agence Nationale de Securite du Medicament et des produits de sante (ANSM)’ on 24/03/2020; approval number MEDAECNAT-2020-01-00038_2019-002407-18.’ Consent N/A References Emile JF, et al., Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX. Eur J Cancer 2017 Sep;82:16–24 Pages, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018 May 26;391(10135):2128–2139.

Published
2020

40. Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study

Author

Julien Taieb, Jean-François Emile, Pierre Laurent-Puig, Magali Svrcek, Dewi Vernerey, Amos Kirilovsky, R. Ben Jannet, Alex Duval, Thierry André, Roger Faroux, Julie Henriques, Jaafar Bennouna, Florence Marliot, Laurent Mineur, Jérôme Galon, Christophe Borg, Franck Pagès, Aurelie Catteau, Jérôme Desramé, Christophe Louvet, Fabienne Hermitte, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Institut Mutualiste de Montsouris (IMM), Institut Sainte Catherine [Avignon], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital privé Jean Mermoz, Service de gastroentérologie (CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon), CHD Vendee (La Roche Sur Yon), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Institut National Du Cancer, INCa: 2012-218 Institut National de la Santé et de la Recherche Médicale, Inserm Ligue Contre le Cancer: AOM09 202 Université Paris Descartes Institut National de la Santé et de la Recherche Médicale, Inserm, This work was supported by the National Institute of Health and Medical Research (INSERM), AP-HP , University Paris Descartes , the Cancéropole Ile-de-France , the Cancer Research for Personalized Medicine (CARPEM), Paris Alliance of Cancer Research Institutes (PACRI), the LabEx Immuno-oncology , [no grant number] the National Cancer Institute of France (INCa, and ref 2012-218), La Ligue Contre le Cancer , the French Ministry of Health Program Hospitalier de Recherche Clinique 2009 (PHRC 2009) [grant number AOM09 202 ] for the IDEA clinical trial, and HalioDx for Immunoscore®.

Subjects
0301 basic medicine, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, Immunoscore, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemotherapy, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Adjuvant therapy, Medicine, Humans, Prospective Studies, predictive, Neoplasm Staging, Duration of Therapy, business.industry, Proportional hazards model, Hazard ratio, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hematology, medicine.disease, Prognosis, Confidence interval, 3. Good health, Oxaliplatin, 030104 developmental biology, Oncology, colon cancer, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Cohort, Colonic Neoplasms, biomarker, Fluorouracil, France, business, prognostic, Cohort study, medicine.drug
Abstract

International audience; Background: The Immunoscore (IS), which prognostically classifies stage I–III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients.Patients and methods: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance.Results: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24–1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23–70.94) for IS Low and 77.14% (95% CI 73.50–80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37–0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6.Conclusions: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. ClinicalTrials.gov registration: NCT03422601; EudraCT Number: 2009-010384-16.

Published
2020

41. Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial

Author

Olivier Bouché, Iman El Hariry, Thierry Lecomte, Thierry André, David Tougeron, Jérôme Cros, Adam Hamm, Jean-Baptiste Bachet, Jean-Philippe Metges, Christine Rebischung, Pascal Hammel, Laurent Mineur, Christophe Tournigand, Christophe Louvet, Farid El Hajbi, Portales Fabienne, Richard Kay, Rosine Guimbaud, Anu Gupta, Roger Faroux, Christelle De La Fouchardiere, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Sainte Catherine [Avignon], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Léon Bérard [Lyon], Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service de chirurgie digestive (CH de La Roche-sur-Yon), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Université Lille Nord de France (COMUE)-UNICANCER, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service de gastroentérologie et cancérologie digestive [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Saint-Antoine [APHP], CRLCC Oscar Lambret, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Cancer Research, Organoplatinum Compounds, Survival, medicine.medical_treatment, Biopsy, Leucovorin, Kaplan-Meier Estimate, Gastroenterology, Deoxycytidine, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Aged, 80 and over, 0303 health sciences, Middle Aged, Progression-Free Survival, 3. Good health, Erythrocyte, Oncology, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor, Fluorouracil, medicine.drug, Adult, Asparaginase, medicine.medical_specialty, Neutropenia, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Pancreatic cancer, Internal medicine, medicine, Humans, Adverse effect, Pancreas, Response Evaluation Criteria in Solid Tumors, 030304 developmental biology, Aged, Neoplasm Staging, Chemotherapy, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Gemcitabine, PHASE IIB TRIAL, Pancreatic Neoplasms, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Pancreatic adenocarcinoma, Follow-Up Studies, Asparagine synthetase
Abstract

International audience; PURPOSE: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.METHODS: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.RESULTS: 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).CONCLUSION: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.

Published
2020

42. Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with advanced pancreatic adenocarcinoma (NCT03665441)

Author

Pascal Hammel, Iman El-Hariry, Teresa Macarulla, Rocio Garcia-Carbonero, Jean-Philippe Metges, Olivier Bouché, Fabienne Portales, Roberto A. Pazo Cid, Laurent Mineur, Antonio Manuel Cubillo Gracian, Isabelle Trouilloud, Rosine Guimbaud, David Tougeron, Juan Jose Reina Zoilo, Jaime Feliu, Tamara Sauri, Christos Fountzilas, Richard Kay, Hagop Youssoufian, and Manuel Hidalgo

Subjects
Cancer Research, Oncology
Abstract

518 Background: Eryaspase, asparaginase encapsulated in red blood cells is an investigational product under development. The encapsulated asparaginase induces the degradation of asparagine and glutamine, crucial for cancer cell growth and survival. An earlier Phase 2b study in patients with advanced pancreatic cancer showed an improvement in overall survival (OS) and progression free survival (PFS) with eryaspase plus chemotherapy. Methods: TRYbeCA-1 was a randomized, open-label Phase 3 trial of eryaspase combined with chemotherapy in patients with advanced adenocarcinoma of the pancreas who have progressed on only one prior line of systemic anti-cancer therapy. Patients were randomized in a 1:1 ratio to gemcitabine/nab-paclitaxel or irinotecan/fluorouracil (5FU) therapy (depending on first-line received) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria included progression on or following first-line systemic treatment, ECOG performance status 0 or 1, stage III-IV disease, documented evidence of disease progression, available tumor tissue and adequate organ function. The primary endpoint was OS. A total of 412 events were required for 90% power to detect a treatment effect hazard ratio (HR) of 0.725 at a two-sided significance level of 5%. Results: A total of 512 patients were included. Baseline characteristics were well balanced between the treatment arms. The study did not meet the OS primary endpoint [HR: 0.92 (95% confidence interval (CI), 0.76-1.11), p-value 0.375]. The median OS for patients treated with eryaspase plus chemotherapy was 7.5 mo (95% CI, 6.5-8.3), compared to 6.7 mo (95% CI, 5.4-7.5) for chemotherapy alone. There was a trend of nominal OS benefit in 107 patients treated with eryaspase and irinotecan-5FU compared to 109 patients in control subgroup, with a median OS of 8.0 mo versus 5.7 mo, respectively [HR: 0.81 (95% CI: 0.60- 1.09)]. Treatment effect was consistent across various prognosis factors. Median PFS was 3.7 mo vs. 3.5 mo in the eryaspase and control arms, respectively [HR: 0.89 (95% CI: 0.73-1.07), p-value 0.215]. Disease control rate was 57.6% and 49.0% (p-value 0.047) in the eryaspase and control arms, respectively. The most common adverse events were in the eryaspase arm were asthenia, diarrhea, and anemia (Grade 3-4: 16.9%, 7.66% and 17.3%, respectively). Eryaspase did not appear to enhance toxicity of chemotherapy. Conclusion: This large prospective study did not meet it primary endpoint of improving OS in patients treated with eryaspase. The addition of eryaspase demonstrated nevertheless a well-tolerated profile and an encouraging survival benefit in the irinotecan/5FU subgroup, warranting further investigation. Clinical trial information: NCT03665441.

Published
2022

44. Panitumumab use in metastatic colorectal cancer and patterns of RAS testing: results from a Europe-wide physician survey and medical records review

Author

George Kafatos, J. Han van Krieken, Parijan Parkar, Jörg Trojan, Etienne Rouleau, Gerald Downey, Giuseppe Aprile, Laurent Mineur, Pilar García-Alfonso, Jiří Tomášek, Pavel Fabian, Giovanna De Maglio, James Bennett, and Gaston Demonty

Subjects
Neuroblastoma RAS viral oncogene homolog, Male, Cancer Research, Colorectal cancer, medicine.disease_cause, Medical Records, GTP Phosphohydrolases, 0302 clinical medicine, Surgical oncology, Surveys and Questionnaires, 030212 general & internal medicine, Neoplasm Metastasis, Practice Patterns, Physicians', medicine.diagnostic_test, Metastatic colorectal cancer, Medical record, Panitumumab, Antibodies, Monoclonal, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Europe, Medical records review, Oncology, mCRC, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Female, KRAS, Guideline Adherence, Colorectal Neoplasms, medicine.drug, Research Article, medicine.medical_specialty, Antineoplastic Agents, lcsh:RC254-282, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Internal medicine, Physicians, Genetics, medicine, Humans, Genetic Testing, Genetic testing, business.industry, Membrane Proteins, medicine.disease, digestive system diseases, business, RAS, Physician survey
Abstract

Background In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies – a physician survey and a medical records review (MRR) – were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice. Methods Both studies enrolled participants from nine European countries and were carried out in three consecutive rounds. Rounds 1 and 2 (2012–2013) examined KRAS (exon 2) testing only; the results have been published in full previously. Round 3 (2014–2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiring KRAS alone to requiring full RAS testing. For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab to patients with mCRC in the previous 6 months. For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients’ records. Results In Round 3, 152 oncologists and 131 patients’ records were included in the physician survey and MRR, respectively. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that panitumumab should only be prescribed in RAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmed KRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only). Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only. Conclusions Physicians’ adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, from KRAS to RAS wild-type mCRC. Additionally, this study demonstrates the uptake of full RAS testing among the majority of oncologists and pathologists. Electronic supplementary material The online version of this article (10.1186/s12885-017-3740-4) contains supplementary material, which is available to authorized users.

Published
2017

45. Myélolipome hépatique : une entité rare, à propos d’un cas et revue de la littérature

Author

Mathieu Gallo, Valérie Costes, Hélène Emptas, Jeanne Ramos, and Laurent Mineur

Subjects
Myelolipoma, Pathology, medicine.medical_specialty, Myeloid, medicine.diagnostic_test, business.industry, medicine.disease, Malignancy, 3. Good health, Pathology and Forensic Medicine, Benign tumor, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Metaplasia, Biopsy, medicine, Bone marrow, medicine.symptom, Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract

Hepatic myelolipoma is a rare entity with only 17 cases described in the literature. A 73mm right liver mass was fortuitously discovered in a 55-year-old man. The biopsy showed normal hepatic tissue adjacent to a normal medular like hematopoietic tissue, showing trilieage hematopoieses, including myeloid cells, erythroid cells and megakaryocytic cells. The diagnosis of hepatic myelolipoma was proposed. This benign tumor was initially described in adrenal gland, which is the most common topography. No malignancy or bleeding complication has been described in its hepatical location. The diagnosis is histological due to non-specific radiological presentation; it allows to avoid a surgical treatment in relation to its excellent prognosis. The etiology is not well established; but some hypotheses are discussed: adrenal or medullar heterotopia, bone marrow embolism, myeloid metaplasia.

Published
2017

46. Erratum to ‘Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial’ [European Journal of Cancer, Volume 124 (January 2020) Pages 91-101]

Author

Fabienne Portales, Olivier Bouché, Roger Faroux, Jérôme Cros, Jean-Philippe Metges, Pascal Hammel, Christine Rebischung, David Tougeron, Christelle De La Fouchardiere, Laurent Mineur, Adam Hamm, Thierry André, Richard Kay, Jean-Baptiste Bachet, Rosine Guimbaud, Christophe Tournigand, Anu Gupta, Iman El Hariry, Thierry Lecomte, Farid El Hajbi, and Christophe Louvet

Subjects
Oncology, Cancer Research, Chemotherapy, medicine.medical_specialty, Asparaginase, Second line treatment, business.industry, medicine.medical_treatment, Cancer, medicine.disease, PHASE IIB TRIAL, chemistry.chemical_compound, Text mining, chemistry, Internal medicine, Pancreatic cancer, Medicine, Open label, business
Published
2020

47. Does A Longer Waiting Period After Neoadjuvant Radio-chemotherapy Improve the Oncological Prognosis of Rectal Cancer?: Three Years' Follow-up Results of the Greccar-6 Randomized Multicenter Trial

Author

Cécile de Chaisemartin, Anne Berger, Guillaume Piessen, Quentin Denost, Jafari Mehrdad, Marine Cachanado, Tabassome Simon, Guillaume Meurette, Yann Parc, Laurent Mineur, Renato Micelli Lupinacci, Philippe Rouanet, Stéphane Benoist, Jérémie H. Lefevre, Anne Dubois, Yves Panis, Frédérique Peschaud, Eddy Cotte, Sylvain Kirzin, Jérôme Loriau, Ben Creavin, Alain Saudemont, Mehdi Karoui, Bernard Meunier, Jean-Jacques Tuech, Nicolas Goasguen, Jérôme Desramé, and Michel Prudhomme

Subjects
Male, medicine.medical_specialty, Time Factors, Colorectal cancer, medicine.medical_treatment, Adenocarcinoma, Waiting period, Disease-Free Survival, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Multicenter trial, Medicine, Humans, Neoplasm Invasiveness, Survival analysis, Radio chemotherapy, Aged, Neoplasm Staging, Analysis of Variance, business.industry, Proctocolectomy, Rectal Neoplasms, Proctocolectomy, Restorative, Chemoradiotherapy, Middle Aged, medicine.disease, Prognosis, Magnetic Resonance Imaging, Survival Analysis, Neoadjuvant Therapy, 3. Good health, Surgery, Clinical trial, Treatment Outcome, 030220 oncology & carcinogenesis, Multivariate Analysis, 030211 gastroenterology & hepatology, Female, business
Abstract

The aim of this study was to report the 3-year survival results of the GRECCAR-6 trial.Current data on the effect of an extended interval between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0) is controversial. Furthermore, its effect on oncological outcomes is unknown.The GRECCAR-6 trial was a phase III, multicenter, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumors of the mid or lower rectum who had received RCT (45-50 Gy with 5-fluorouracil or capecitabine) were included and randomized into a 7- or 11-week waiting period. Primary endpoint was the pCR rate. Secondary endpoints were 3-year overall (OS), disease-free survival (DFS), and recurrence rates.A total of 265 patients from 24 participating centers were enrolled. A total of 253 patients underwent a mesorectal excision. Overall pCR rate was 17% (43/253). Mean follow-up from surgical resection was 32 ± 8 months. Twenty-four deaths occurred with an 89% OS at 3 years. DFS was 68.7% at 3 years (75 recurrences). Three-year local and distant recurrences were 7.9% and 23.8%, respectively. The randomization group had no impact on the 3-year OS (P = 0.8868) or DFS (P = 0.9409). Distant (P = 0.7432) and local (P = 0.3944) recurrences were also not influenced by the waiting period. DFS was independently influenced by 3 factors: circumferential radial margin (CRM) ≤1 mm [hazard ratio (HR) = 2.03; 95% confidence interval (CI), 1.17-3.51], ypT3-T4 (HR = 2.69; 95% CI, 1.19-6.08) and positive lymph nodes (HR = 3.62; 95% CI, 1.89-6.91).Extending the waiting period by 4 weeks following RCT has no influence on the oncological outcomes of T3/T4 rectal cancers.

Published
2019

48. Efficacy and Safety of Bevacizumab Combined With First-Line Chemotherapy in Elderly (≥75 Years) Patients With Metastatic Colorectal Cancer: A Real-World Study

Author

Stefano Kim, Denis Smith, Alexandre Tanang, Eric Francois, Florence Rollot, Yoann Lelarge, Kalaivani Veerabudun, P. Laplaige, Gael Deplanque, Miruna Ionescu-Goga, Sophie Gourgou, and Laurent Mineur

Subjects
Male, medicine.medical_specialty, Bevacizumab, Colorectal cancer, Population, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, Prospective Studies, education, Adverse effect, Stroke, Geriatric Assessment, Aged, Aged, 80 and over, education.field_of_study, business.industry, Gastroenterology, Age Factors, medicine.disease, Primary tumor, Confidence interval, Progression-Free Survival, Clinical trial, Hemorrhagic Stroke, Oncology, 030220 oncology & carcinogenesis, Mesenteric Ischemia, 030211 gastroenterology & hepatology, Female, France, business, Colorectal Neoplasms, medicine.drug
Abstract

Although elderly patients are the first concerned by colorectal cancer (CRC), they are underrepresented in clinical trials. The real-world CASSIOPEE study was thus conducted in elderly patients treated for metastatic CRC (mCRC).This French prospective, multicenter, noninterventional study aimed to estimate 1-year progression-free survival (PFS) and overall survival (OS), and describe treatments, patient autonomy (Instrumental Activities of Daily Living; Balducci scale), and safety over 24 months, in patients older than 75 with mCRC, starting first-line bevacizumab plus chemotherapy (NCT01555762).From 2012 to 2014, 402 patients were included (safety population: n = 383, efficacy population: n = 358). Patient characteristics were as follows: mean age, 81 ± 4 years (80 years, 46%; 80-85 years, 44%;85 years, 10%); men, 52%; colon primary tumor, 80%; main metastatic site, liver 66%; Eastern Cooperative Oncology Group performance 0-1, 81%. Median PFS was 9.1 months (95% confidence interval [CI]: 8.3-10.2). It was superior for patients ≤85 years (80 years: 9.3 months; 80-85 years: 9.5 months) compared with patients85 years (8.3 months). Median OS was 19.0 months (95% CI, 16.5-21.5) and decreased in the 2 oldest groups (20.6, 17.8, and 13.0 months). Autonomy assessments decreased over time leading to nonconclusive results. Twenty-six percent of patients experienced serious adverse events (SAEs): 7% bevacizumab-related SAEs, and 6% bevacizumab-targeted SAEs. Two fatal bevacizumab-related adverse events were reported (hemorrhagic stroke and intestinal ischemia).This large French real-world study showed that medically fit older patients with mCRC could have a benefit/risk balance similar to that of younger patients when treated with first-line bevacizumab plus chemotherapy. Improvements in geriatric assessments are needed to better define this population.

Published
2019

49. Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

Author

Laurent Mineur, Charles Decraene, Nicolas Kiavue, Simon Thezenas, François Ghiringhelli, Olivier Bouché, Eric Francois, Adrien Saliou, Marc-Henri Stern, Driffa Moussata, Faiza Khemissa-Akouz, Charlotte Proudhon, Marc Ychou, Thibault Mazard, Jean-Yves Pierga, François-Clément Bidard, Jordan Madic, Rosine Guimbaud, Luc Cabel, Aurore Rampanou, Michel Rivoire, Trevor Stanbury, Pascale Mariani, Institut Curie [Paris], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Saclay, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Léon Bérard [Lyon], Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Toulouse [Toulouse], Institut Sainte Catherine [Avignon], Centre Hospitalier Saint Jean de Perpignan, Département d'hépato-gastro-entérologie [Hôpital Trousseau : CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), R&D Unicancer [Paris], CRLCC Val d'Aurelle - Paul Lamarque, Herrada, Anthony, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-CHU Trousseau [APHP]

Subjects
0301 basic medicine, Oncology, FOLFIRINOX, Colorectal cancer, medicine.medical_treatment, Kaplan-Meier Estimate, medicine.disease_cause, Targeted therapy, 0302 clinical medicine, Circulating tumor cell, Medicine, Digital polymerase chain reaction, Prospective Studies, Neoplasm Metastasis, lcsh:QH301-705.5, circulating tumor DNA, metastatic colorectal cancer, General Medicine, Middle Aged, Neoplastic Cells, Circulating, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, KRAS, Colorectal Neoplasms, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, circulating tumor cells, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Liquid biopsy, neoplasms, Aged, Chemotherapy, liquid biopsy, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030104 developmental biology, lcsh:Biology (General), Mutation, business
Abstract

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch&reg, ) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (&ge, 3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p &lt, 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

Published
2019

50. Rationale and Design of the IROCAS Study: Multicenter, International, Randomized Phase 3 Trial Comparing Adjuvant Modified (m) FOLFIRINOX to mFOLFOX6 in Patients With High-Risk Stage III (pT4 and/or N2) Colon Cancer—A UNICANCER GI-PRODIGE Trial

Author

Loïc Campion, Florence Borde, Sandrine Hiret, Claire Jouffroy, Laurent Mineur, Sharlene Gill, Petr Kavan, You-Heng Lam, Pascal Artru, Laurent Miglianico, Timothy R. Asmis, Olivier Bouché, Laetitia-Shana Rajpar, Yann Touchefeu, Julien Taieb, Jean-François Emile, Thierry André, Jaafar Bennouna, Sorbonne Université (SU), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Sainte Catherine [Avignon], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Louis Pasteur [Chartres], UNICANCER, and University of British Columbia (UBC)

Subjects
medicine.medical_specialty, Randomization, Organoplatinum Compounds, Colorectal cancer, FOLFIRINOX, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Leucovorin, Adenocarcinoma, Irinotecan, Gastroenterology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Medicine, Humans, 030212 general & internal medicine, Neoplasm Staging, business.industry, medicine.disease, 3. Good health, Oxaliplatin, Survival Rate, Regimen, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Colonic Neoplasms, Fluorouracil, business, Adjuvant, medicine.drug
Abstract

Background According to the IDEA trial, 6-month adjuvant chemotherapy should remain the treatment standard in stage III T4 or N2 colon cancer. The relatively poor survival in this high-risk subgroup—a 3-year disease-free survival (DFS) rate of 65%—and the potential synergistic efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan suggest that FOLFIRINOX may be a regimen of particular interest in this setting. Patients and Methods This multicenter international phase 3 trial (ClinicalTrials.gov NCT02967289 ) being conducted in 49 centers in France and Canada plans to randomize (1:1; minimization method) 640 patients aged 18 to 70 years with Eastern Cooperative Oncology Group performance status ≤ 1. Randomization occurs within 42 days (with treatment initiated within 56 days) after curative-intent R0 surgical resection of a pT4N1 or pT1-4N2 colon adenocarcinoma. Patients will be randomized to receive adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, and 5-FU 2.4 g/m2 over 46 hours) or modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU bolus 400 mg/m2, then 2.4 g/m2 over 46 hours) every 2 weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. A gain of 9% in 3-year DFS (primary end point) is expected (74% in the experimental arm vs. 65% in the control arm; α, 5% [2-sided log-rank test]; 1-β, 80%). Secondary end points of this study include 2-year DFS, overall survival, and toxicity.

Published
2019

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