Publications by authors named "Gaetan des Guetz"

41 Publications

First-line immune-checkpoint inhibitor plus chemotherapy chemotherapy alone for extensive-stage small-cell lung cancer: a meta-analysis.

Ther Adv Med Oncol 2020 9;12:1758835920977137. Epub 2020 Dec 9.

Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Introduction: Platin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest.

Methods: This meta-analysis was conducted on randomized trials comparing first-line ICI+CT CT alone for ES-SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12 months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis.

Results: The literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck 2016) that included 2775 patients (66% males, 95% smokers, median age: 64 years, PS = 0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75-0.89);  <  0.00001] and PFS [0.81 (0.75-0.87);  <  0.00001], with OS benefits for anti-PD-L1 [0.73 (0.63-0.85);  < 0.0001] or anti-PD-1 [0.76 (0.63-0.93);  < 0.006] but not for anti-CTLA-4 [0.90 (0.80-1.01),  = 0.07]. ORRs for ICI+CT or CT alone were comparable [odds ratio 1.12 (0.97-1.00);  = 0.12], but responses at 12 months favored ICI+CT [4.16 (2.81-6.17),  < 0.00001]. Serious grade-3/4 AEs were more frequent with ICI+CT [odds ratio 1.18 (1.02-1.37);  = 0.03]. Compared with CT, no ICI+CT benefit was found for ES-SCLC with brain metastases at diagnosis [HR 1.14 (0.87-1.50); =0.34].

Conclusions: First-line ICI+CT appears to be superior to CT alone for ES-SCLC except for patients with brain metastases at diagnosis.
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http://dx.doi.org/10.1177/1758835920977137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731693PMC
December 2020

Immune Checkpoint Inhibitors for Patients Aged ≥ 75 Years with Advanced Cancer in First- and Second-Line Settings: A Meta-Analysis.

Drugs Aging 2020 10;37(10):747-754

Department of Medical Oncology, UCOG Paris Nord, AP-HP, Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75010, Paris, France.

Background: The impact of aging on the effectiveness of immune checkpoint inhibitors (ICIs) remains controversial, and little is known on the subject in adults aged ≥ 75 years.

Objective: The objective of this comprehensive meta-analysis was to assess the efficacy of ICIs in patients aged ≥ 75 years.

Methods: We performed a meta-analysis of published randomized controlled trials concerning ICIs (as monotherapy or in combination) versus standard therapy in patients with advanced solid tumors between January 2010 and January 2020. We compared overall survival between older (aged ≥ 75 years) and younger (< 75 years) patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected and pooled. The secondary endpoint focused on the impact of the use of ICIs in first- and second-line settings.

Results: In total, 15 phase III studies evaluating anti-programmed cell death 1 (anti-PD-1) (nivolumab or pembrolizumab), anti-programmed cell death ligand 1 (anti-PD-L1) (atezolizumab or avelumab), or anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) (ipilimumab) therapies were included. Enrolled patients had non-small-cell lung cancer, renal cell carcinoma, melanoma, head and neck squamous cell carcinoma, or gastric cancer. Eight studies assessed treatment in the first-line setting and seven in the second-line setting. The median age was 64 years, with 906 patients aged ≥ 75 years (552 in first line, 354 in second line) and 8741 were aged < 75 years (4992 in first line, 3749 in second line). In the first-line setting, HRs for death were 0.78 (95% CI 0.61-0.99) in patients aged ≥ 75 years versus 0.84 (95% CI 0.71-1.00) in those aged < 75 years. In the second-line setting, HRs for death were 1.02 (95% CI 0.77-1.36) in patients aged ≥ 75 years versus 0.68 (95% CI 0.61-0.75) in those aged < 75 years, with a statistically significant difference observed between subgroups (p = 0.009 for interaction).

Conclusions: ICIs appear to be effective in patients aged ≥ 75 years. However, the survival benefit is mainly observed in first-line treatment and remains unclear in the second-line setting.
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http://dx.doi.org/10.1007/s40266-020-00788-5DOI Listing
October 2020

First-line angiogenesis inhibitor plus erlotinib versus erlotinib alone for advanced non-small-cell lung cancer harboring an EGFR mutation.

J Cancer Res Clin Oncol 2020 Dec 7;146(12):3333-3339. Epub 2020 Jul 7.

Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Purpose: Erlotinib is indicated as first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor-receptor (EGFR) mutation. Addition of a vascular endothelial growth factor (VEGF) inhibitor (anti-VEGF) in combination with the tyrosine-kinase inhibitor erlotinib in this setting is controversial.

Methods: We conducted a meta-analysis of randomized trials comparing anti-VEGF plus erlotinib vs erlotinib alone as first-line therapy for advanced NSCLC harboring an EGFR mutation. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and median duration of response (DOR). A fixed-effect model was used.

Results: Four studies evaluated bevacizumab + erlotinib (ARTEMIS, NEJ026, J025667, Stinchcombe et al.), and another evaluated ramucirumab + erlotinib (RELAY). These five eligible studies included 1230 non-squamous NSCLC patients, 654 (53.2%) with exon 19 deletion (ex19del) and 568 (46.8%) with EGFR. Patients were predominantly women (63%), Asians (85%) and non-smokers (60%); the median age was 64 years. The combination (anti-VEGF + erlotinib) was significantly associated with prolonged PFS (hazards ratio [HR] 0.59 [95% confidence interval (CI) 0.51-0.69]; p < 0.00001). The combination achieved significantly longer median DOR (p < 0.005). Based on interim analyses, OS (HR 0.90 [0.68-1.19]; p = 0.45) and ORR (odds ratio 1.19 [95% CI 0.91-1.55]; p = 0.21 were comparable.

Conclusions: For patients with untreated, advanced, EGFR-mutation-harboring NSCLCs, the anti-VEGF + erlotinib combination, compared to erlotinib alone, was associated with significantly prolonged PFS but mature data for OS are needed to confirm the benefit of this strategy.
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http://dx.doi.org/10.1007/s00432-020-03311-wDOI Listing
December 2020

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD.

J Geriatr Oncol 2020 11 22;11(8):1255-1262. Epub 2020 Apr 22.

Gastroenterology and Digestive Oncology Department, University Hospital Dijon, Dijon, France; EPICAD INSERM LNC-UMR 1231, Université de Bourgogne et Franche Comté, Dijon, France.

Background: Regorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities.

Objectives: to assess the efficacy and safety of regorafenib at it's approved dose in the older population.

Patients And Methods: This multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off).

Results: Forty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3-4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy.

Conclusion: Treatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy.
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http://dx.doi.org/10.1016/j.jgo.2020.04.001DOI Listing
November 2020

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).

Oncologist 2020 02 2;25(2):e266-e275. Epub 2019 Oct 2.

Department of Gastroenterology, Cochin Hospital, Paris, France.

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.
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http://dx.doi.org/10.1634/theoncologist.2019-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011620PMC
February 2020

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study.

Int J Cancer 2020 07 13;147(1):285-296. Epub 2020 Feb 13.

Sorbonne University and Medical Oncology Department, Saint Antoine Hospital, Paris, France.

Mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression-free survival (PFS) in a population receiving first-line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first-line chemotherapy were 6.0 and 26.3 months, respectively. For second-line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan-based chemotherapy compared to oxaliplatin-based chemotherapy. The association was no longer statistically significant using IPTW methodology. In multivariable analysis, anti-VEGF as compared to anti-EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00-3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first-line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti-VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors.
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http://dx.doi.org/10.1002/ijc.32879DOI Listing
July 2020

First-line PD-1/PD-L1 inhibitor plus chemotherapy vs chemotherapy alone for negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers.

J Cancer Res Clin Oncol 2020 Feb 4;146(2):441-448. Epub 2019 Nov 4.

Service de Pneumologie, Centre Hospitalier Intercommunal (CHI) Créteil, Créteil, France.

Aims: Single-agent anti-PD-1/PD-L1 clinical efficacy against < 1% PD-L1-expressing non-small-cell lung cancers (NSCLCs) is controversial.

Methods: This meta-analysis examined randomized-trial data comparing first-line PD-1/PD-L1-inhibitor + chemotherapy (CT) vs CT alone for advanced < 1% PD-L1 NSCLCs. Outcome measures included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR).

Results: IMpower (atezolizumab + CT), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001).

Conclusions: First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L1-expressing NSCLCs for OS, PFS and ORR.
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http://dx.doi.org/10.1007/s00432-019-03070-3DOI Listing
February 2020

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer.

World J Gastroenterol 2019 Aug;25(29):4007-4018

Oncology Department, Avicenne Hospital, Bobigny 93000, France.

Background: Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown.

Aim: To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management.

Methods: Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up.

Results: Overall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low.

Conclusion: The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient's quality of life appeared to be limited.
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http://dx.doi.org/10.3748/wjg.v25.i29.4007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689814PMC
August 2019

Is There a Benefit of Addition Docetaxel, Abiraterone, Celecoxib, or Zoledronic Acid in Initial Treatments for Patients Older Than 70 Years With Hormone-sensitive Advanced Prostate Cancer? A Meta-analysis.

Clin Genitourin Cancer 2019 08 13;17(4):e806-e813. Epub 2019 May 13.

Department of Medical Oncology, UCOG, AP-HP, Saint-Louis Hospital, Paris, France; Paris Diderot University, Paris, France.

Background: Results from large randomized controlled trials combining docetaxel, abiraterone, celecoxib, or bisphosphonates with androgen deprivation therapy (ADT) in hormone-sensitive prostate cancer have emerged. However, in our knowledge, few data are available in patients older than 70 years. Therefore, we undertook a meta-analysis of all published phase III studies.

Materials And Methods: We performed a PubMed search using the keywords: "hormone sensitive prostate cancer," "phase III studies," "docetaxel," "abiraterone," "celecoxib," and "bisphosphonates." We also screened American Society of Clinical Oncology and European Society for Medical Oncology proceedings. Combination therapies were compared with ADT alone. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. A hazard ratio of less than 1.00 favored the combination group.

Results: This meta-analysis included 8 studies: 3 assessed docetaxel (CHAARTED, STAMPEDE arm E and C), 2 others assessed abiraterone (LATITUDE and STAMPEDE arm G); 2 others assessed celecoxib (STAMPEDE arm D and F), and the last one assessed zoledronic acid alone (STAMPEDE arm B). Our meta-analysis included 2264 patients (86% with metastases). Concerning age, we chose a cutoff of 70 years, corresponding to the available data for each study. The performance index was 0 to 1 for about 90% of patients. Overall, in patients > 70 years old, the addition of docetaxel statistically improved PFS (HR, 0.51; 95% CI, 0.42-0.61) but not OS (HR, 0.86; 95% CI, 0.69-1.07). The addition of abiraterone to ADT also statistically improved PFS (HR, 0.49; 95% CI, 0.37-0.64) but not OS (HR, 0.85; 95% CI, 0.67-1.08), as well as the addition of celecoxib (HR, 0.67; 95% CI, 0.53-0.85 and HR, 0.95; 95% CI, 0.73-1.25, respectively). The addition of zoledronic acid did not improve PFS or OS (HR, 0.78; 95% CI, 0.61-1.00 and HR, 0.99; 95% CI, 0.71-1.38, respectively).

Conclusions: The addition of docetaxel, abiraterone, or celecoxib to ADT significantly increased PFS in older men with hormone-sensitive advanced prostate cancer. However, the benefit in OS is not statistically significant. Further studies are needed to define the best first-line strategy in this subgroup.
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http://dx.doi.org/10.1016/j.clgc.2019.05.001DOI Listing
August 2019

Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer: The UNICANCER PRODIGE18 Randomized Clinical Trial.

JAMA Oncol 2019 01;5(1):83-90

Department of Medical Oncology, Centre Hospitalier Universitaire de Besançon, Besançon, France.

Importance: Second-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer.

Objective: To evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy.

Design, Setting, And Participants: A prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population.

Interventions: Patients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover).

Main Outcomes And Measures: The primary end point was the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS.

Results: A total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95% CI, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2-6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46-1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors.

Conclusions And Relevance: The results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.

Trial Registration: ClinicalTrials.gov identifier: NCT01442649 and clinicaltrialsregister.eu identifier: EUDRACT 2009-012942-22.
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http://dx.doi.org/10.1001/jamaoncol.2018.4465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440242PMC
January 2019

Impact of the addition of bevacizumab, oxaliplatin, or irinotecan to fluoropyrimidin in the first-line treatment of metastatic colorectal cancer in elderly patients.

Int J Colorectal Dis 2018 Aug 21;33(8):1125-1130. Epub 2018 Apr 21.

Department of Biostatistics, Fédération Française de Cancérologie Digestive, Dijon, France.

Introduction: The clinical benefit of double-front-line therapy (including oxaliplatin or irinotecan or bevacizumab plus 5-fluorouracil (5FU) or capecitabine) compared to monotherapy (5FU or capecitabine) in elderly (> 70 years) patients with metastatic colorectal cancer (MCRC) is controversial. We performed a meta-analysis of published randomized studies.

Materials And Methods: The selection of the studies was carried out using PubMed with the following keywords: "metastatic colorectal cancer," "elderly," "oxaliplatin," "irinotecan," "bevacizumab," "survival." The efficacy endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. By convention, an HR < 1 was a result in favor of biotherapy.

Results: This meta-analysis (MA) included ten studies: three assessing irinotecan (FFCD 2001-02, CAIRO, and an already published MA by Folprecht), three assessing oxaliplatin (FOCUS2, FFCD 2000-05, and a published study by De Gramont), and four assessing bevacizumab (PRODIGE-20, AVEX, AGITG-MAX, and "AVF2192g" by Kabbinavar). Our MA included 1652 patients (62% of men). Concerning age, we chose a cut-off of 70 years or a cut-off of 75 years, corresponding to the available data for each study. The performance index (PS) was 0-1 for about 90% of patients, with the exception of FFCD 2001-02 and FOCUS2 which included 30% of patients with PS2. Overall, the addition of bevacizumab to fluoropyrimidin statistically improves both OS and PFS (HR = 0.78; CI 0.63-0.96 and HR = 0.55; CI 0.44-0.67, respectively). The addition of oxaliplatin did not statistically improve OS (= 0.99; CI 0.85-1.17) but improves PFS (HR = 0.81; CI 0.67-0.97) as well as the addition of irinotecan (HR = 1.01; CI 0.84-1.22 and HR = 0.82; CI 0.68-1.00, respectively).

Conclusion: In previously untreated elderly patients with MCRC, the addition of bevacizumab to fluoropyrimidin appears more effective in terms of OS or PFS than the addition of oxaliplatin or irinotecan.
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http://dx.doi.org/10.1007/s00384-018-3053-3DOI Listing
August 2018

Esophageal tumors

Rev Prat 2017 04;67(4):e189-e195

CHU de Limoges, hôpital Dupuytren, 87042 Limoges Cedex, France.

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April 2017

Perioperative chemotherapy with FOLFOX in resectable gastroesophageal adenocarcinoma in real life practice: An AGEO multicenter retrospective study.

Dig Liver Dis 2016 Dec 9;48(12):1498-1502. Epub 2016 Aug 9.

Gastroenterology and Digestive Oncology Department, Avicenne Hospital, APHP and Université Paris 13, Sorbonne Paris Cité, Bobigny, France.

Purpose: Perioperative chemotherapy with 5-fluorouracil and cisplatin, with or without epirubicin, improves overall survival in resectable gastroesophageal junction and gastric adenocarcinoma. The aim of this retrospective multicenter study was to evaluate the safety and efficacy of perioperative chemotherapy with a FOLFOX-based regimen.

Patients And Methods: We enrolled patients with resectable gastric or gastroesophageal adenocarcinoma, who had at least 3 cycles of a pre-operative FOLFOX-based regimen. The primary end point was the feasibility of the peri-operative chemotherapy.

Results: We enrolled 109 patients from 2007 to 2012 in 12 centres. Their median age was 66, 67% were men and 73% had gastric tumours. The median number of chemotherapy courses was 6 with a median of 4 pre-operative cycles and 2 post-operative cycles. Twenty-three patients received at least 8 cycles of chemotherapy. In univariate analysis, the Karnofsky index at inclusion was the only factor associated with 8 cycles of chemotherapy. An R0 resection was achieved in 100 patients (95.2%).

Conclusion: The FOLFOX-based perioperative regimen achieves favourable results in real life practice. The optimal number of chemotherapy cycle remains to be determined. FOLFOX regimen may be used as an alternative treatment option to a cisplatin-based regimen in resectable gastroesophageal adenocarcinoma. A prospective randomized trial is needed to confirm these results.
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http://dx.doi.org/10.1016/j.dld.2016.07.022DOI Listing
December 2016

Efficacy of Adjuvant Chemotherapy in Colon Cancer With Microsatellite Instability: A Large Multicenter AGEO Study.

J Natl Cancer Inst 2016 Jul 1;108(7). Epub 2016 Feb 1.

Affiliations of authors: Department of Gastroenterology (DT, GS, CS), Department of Medical Oncology (AF), and Department of Molecular Oncology (LKT), Poitiers University Hospital , Poitiers , France ; Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC) - EA 4331, Poitiers University , Poitiers (DT, CS); Methodology and Quality of Life in Oncology Unit, Besançon University Hospital , Besançon , France (GM); Department of Gastroenterology, Ambroise Paré Hospital , Boulogne-Billancourt , France (IT); Department of Gastroenterology (TL) and Department of Biochemistry (JCP), Tours University Hospital , Tours , France , UMR GICC CNRS 7292, Tours François Rabelais University, Tours (TL); Paris Descartes University, Cochin Hospital , Paris , France (RC); Department of Gastroenterology (TA) and Department of Medical Oncology (CDG), Avicenne Hospital , Bobigny , France ; Department of Gastroenterology, Bordeaux Nord Aquitaine Clinic , Bordeaux , France (CL); Department of Gastroenterology, Jean Mermoz Lyon Hospital , Lyon , France (PA); Department of Gastroenterology, Nantes University Hospital , Nantes , France (EC, TMB); Department of Gastroenterology, Rouen University Hospital , Rouen , France (DS, PM); Department of Medical Oncology, Saint-Antoine Hospital , Paris , France (TB); Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, APHP , Paris , France (JT, AZ); Paris Descartes University, Sorbonne Paris Cité , Paris , France (RC, JT, AZ).

Background: Deficient mismatch repair (dMMR) colon cancer (CC) is reportedly resistant to 5-fluorouracil (5FU) adjuvant chemotherapy while preliminary data suggest chemosensitivity to oxaliplatin. We assessed the efficacy of fluoropyrimidine with and without oxaliplatin in a large cohort of dMMR CC patients.

Methods: This retrospective multicenter study included all consecutive patients who underwent curative surgical resection for stage II or III dMMR CC between 2000 and 2011. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided.

Results: A total of 433 dMMR CC patients were included (56.8% stage II, 43.2% stage III). Mean follow-up was 47.0 months. The patients received surgery alone (n = 263) or surgery plus adjuvant chemotherapy consisting of fluoropyrimidine with (n = 119) or without (n = 51) oxaliplatin. Adjuvant chemotherapy was administered to 16.7% of stage II and 69.0% of stage III CC patients. As compared with surgery alone, adjuvant oxaliplatin-based chemotherapy improved disease-free survival (DFS) in multivariable analysis (HR = 0.35, 95% CI = 0.19 to 0.65, P < .001), contrary to adjuvant fluoropyrimidine alone (HR = 0.73, 95% CI = 0.36 to 1.49, P = .38). In the subgroup analysis, the DFS benefit of oxaliplatin-based chemotherapy was statistically significant in multivariable analysis only in stage III (HR = 0.41, 95% CI = 0.19 to 0.87, P = .02).

Conclusion: This study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin in stage III dMMR CC.
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http://dx.doi.org/10.1093/jnci/djv438DOI Listing
July 2016

Chronological Age and Risk of Chemotherapy Nonfeasibility: A Real-Life Cohort Study of 153 Stage II or III Colorectal Cancer Patients Given Adjuvant-modified FOLFOX6.

Am J Clin Oncol 2018 Jan;41(1):73-80

IMRB-EA 7376 CEpiA Clinical Epidemiology And Ageing, Faculty of Medicine, A-TVB DHU.

Objectives: To assess nonfeasibility of adjuvant-modified FOLFOX6 chemotherapy in patients with stage II or III colorectal cancer.

Methods: Consecutive patients managed between 2009 and 2013 in 2 teaching hospitals in the Paris urban area were included in the CORSAGE (COlorectal canceR, AGe, and chemotherapy fEasability study) cohort study. Nonfeasibility was defined by the frequencies of empirical first-cycle dose reduction (>15%), early discontinuation (<12 cycles), and low relative dose intensity (RDI) (<0.85). Risk factors for chemotherapy nonfeasibility were identified using multivariate logistic regression.

Results: Among 153 patients, 56.2% were male (median age, 65.6 y; 35.3%≥70 y; 7.3% with performance status [PS]≥2). For 5-fluorouracil (5-FU), 20.9% of patients had first-cycle dose reduction and 28.1% early discontinuation; RDI was 0.91 (25th to 75th percentiles, 0.68 to 0.99). Factors independently associated with first-cycle 5-FU dose reduction were aged 65 to 69 years versus those younger than 65 years (adjusted odds ratio [aOR], 5.5; 95% confidence interval [CI], 1.5-19.9) but not age 70 years and older, PS≥2 (aOR, 6.02; 95% CI, 1.15-31.4), higher Charlson Comorbidity Index (aOR1-point increase, 1.4; 95% CI, 1.05-1.82), or larger number of medications (aOR 1-medication increase, 1.19; 95% CI, 1.00-1.42). Oxaliplatin dose reduction occurred in 52.3% of patients and early discontinuation in 62.7%; the latter was more common in the 70 years and older group (92.6% vs. 74.6% in the <65-y group; P=0.01); RDI was 0.7 (95% CI, 0.55-0.88).

Conclusions: In the real-world setting, compared with their younger and older counterparts, patients aged 65 to 69 years given modified FOLFOX6 for stage II or III colorectal cancer had higher frequencies of 5-FU nonfeasibility defined based on first-cycle dose reduction, early discontinuation, and RDI; and these differences were independent from PS, comorbidities, and number of medications.
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http://dx.doi.org/10.1097/COC.0000000000000233DOI Listing
January 2018

Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis.

Int J Colorectal Dis 2015 Oct 23;30(10):1305-10. Epub 2015 Jun 23.

Unité de Coordination en Onco-Gériatrie UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France.

Background: The clinical benefit of first-line doublet chemotherapy (including oxaliplatin or irinotecan) compared to single-drug therapy (5FU) in elderly patients (>70 or >75 years old) with metastatic colorectal cancer (MCRC) is controversial. Therefore, we undertook a meta-analysis of all published phase III studies.

Material And Methods: We performed a PubMed search using keywords metastatic colorectal cancer, phase III studies, oxaliplatin, irinotecan, survival. We also screened Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) proceedings. Few studies have been published corresponding to our inclusion criteria. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Toxicity was also examined when available. Hazard ratios (HRs) with their 95 % confidence intervals (CI) were collected from the studies and pooled. By convention, HRs <1 corresponded to a better outcome for doublets. p values <0.05 were considered statistically significant. A fixed-effect model was used. We used Comprehensive Meta-Analysis Software (Biostat, Englewood, NJ, USA).

Results: This meta-analysis (MA) included five original studies (Mitry and Venderbosch for CAIRO both assessing irinotecan, De Gramont and Seymour for FOCUS2 and Ducreux assessing oxaliplatin) and an already published MA (Folprecht) of four trials comparing FOLFIRI with 5FU (Saltz, Douillard, Köhne and Seymour). Our MA included 1225 patients (70 % men). For age, we chose a cut-off of 70 years for oxaliplatin and a cut-off of 75 years for irinotecan. The performance status (PS) score was 0-1 in about 90 % of patients except for the studies by Mitry and Seymour FOCUS2 which both included 30 % of PS2 patients. Overall, doublet chemotherapy, compared to 5FU alone, did not improve OS (HR = 1.00; CI: 0.89-1.13) but significantly improved PFS (HR = 0.82; CI: 0.72-0.93). When assessed separately, FOLFIRI and FOLFOX both significantly improved PFS (HR = 0.83; 0.68-1.00 and HR = 0.81; 0.68-0.97, respectively). The main grade 3-4 toxicities for FOLFIRI were diarrhoea, nausea, vomiting and neutropenia, which occurred significantly more often than with 5FU alone.

Conclusion: Addition of oxaliplatin or irinotecan to 5FU in metastatic CRC significantly improved PFS in elderly patients more than 70 years old but was associated with an increased risk of toxicity as shown for irinotecan.
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http://dx.doi.org/10.1007/s00384-015-2296-5DOI Listing
October 2015

Is There a Survival Benefit of First-Line Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor Monotherapy Versus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer?: A Meta-Analysis.

Target Oncol 2016 Feb;11(1):41-7

Department of Oncology, Avicenne Hospital, HUPSSD, AP-HP, 125 route de Stalingrad, 93009, Bobigny, France.

Background: Tyrosine-kinase inhibitors (TKIs) markedly improve progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) mutated for epidermal growth factor receptor (EGFR). Results on overall survival (OS) are less clear-cut. We performed a publication-based meta-analysis to address further this issue.

Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, tyrosine kinase inhibitors, epidermal growth factor receptor mutation, survival, and randomized controlled trials). We also searched for relevant abstracts in annual proceedings of ASCO, ESMO, and WCLC meetings. We cross-checked all references from all eligible articles. Only phase III randomized controlled trials comparing TKI monotherapy and platinum-based doublet chemotherapy in first-line treatment of metastatic or advanced NSCLC were included. We used EasyMA software to perform statistical analyses. A random effect model was used in case of heterogeneity between studies (and a fixed effect model in absence of heterogeneity).

Results: The eight eligible studies included 2962 patients (780 males, 2182 females, mostly Asian, median age 60 years), 2909 adenocarcinomas (98 %), 1739 mutated tumors (897 exon 19 deletion, 699 L858 mutation), 448 stage IIIB, and 2222 stage IV (75 %) tumours and 2453 never smokers (83 %). Four studies assessed gefitinib, two studies assessed erlotinib, and two studies assessed afatinib. Chemotherapies were doublets including a platinum salt. All studies included patients with EGFR mutations, but six studies included only EGFR mutated patients. OS was similar among patients who first received TKI or chemotherapy (HR 0.98, 95 % CI 0.87-1.10, fixed effect model). Conversely, compared with chemotherapy, EGFR TKIs significantly improved PFS in patients with EGFR-mutated tumours (HR 0.37, 95 % CI 0.29-0.49, random effect model). Concerning side effects, rash (RR 6.29, 95 % CI 4.05-9.77), diarrhoea (RR 3.51, 95 % CI 2.15-5.75), stomatitis (RR 3.57, 95 % CI 1.81-7.04), and interstitial lung disease (RR 6.07, 95 % CI 1.66-22.2) were significantly more frequent after TKIs. As expected, fatigue (RR 0.38, 95 % CI 0.32-0.45), nausea/vomiting (RR 0.19, 95 % CI 0.11-0.32), and haematological disorders, including thrombocytopenia (RR 0.18, 95 % CI 0.09-0.35), anaemia (RR 0.22, 95 % CI 0.15-0.33), and grade 3-4 neutropenia (RR 0.06, 95 % CI 0.04-0.08), were significantly more frequent after chemotherapy.

Conclusion: The major discrepancy between a similar OS and a markedly improved PFS after first-line TKI compared with chemotherapy could be related to the high level of crossing-over between both groups.
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http://dx.doi.org/10.1007/s11523-015-0373-xDOI Listing
February 2016

Similar survival rates with first-line gefitinib, gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced non-small cell lung cancer and a poor performance status (IFCT-0301).

J Geriatr Oncol 2015 May 16;6(3):233-40. Epub 2015 Feb 16.

Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France.

Objectives: We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS).

Materials And Methods: Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age.

Results: Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged <70years (younger, n=56) and ≥70years (older, n=71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non-smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1-1.9) for younger compared to 2.3months (95% CI: 2.1-2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5-2.4) and 3.7months (95% CI: 2.4-4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients (p=0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38-0.85) for the elderly compared to patients aged <70years (p=0.004).

Conclusions: Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged ≥70years with a PS of 2.
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http://dx.doi.org/10.1016/j.jgo.2015.02.002DOI Listing
May 2015

Impact of physical activity on cancer-specific and overall survival of patients with colorectal cancer.

Gastroenterol Res Pract 2013 3;2013:340851. Epub 2013 Oct 3.

Department of Medical Oncology, APHP, Avicenne Hospital, 125 route de Stalingrad, 125 rue de Stalingrad, 93009 Bobigny, France.

Background. Physical activity (PA) reduces incidence of colorectal cancer (CRC). Its influence on cancer-specific (CSS) and overall survival (OS) is controversial. Methods. We performed a literature-based meta-analysis (MA) of observational studies, using keywords "colorectal cancer, physical activity, and survival" in PubMed and EMBASE. No dedicated MA was found in the Cochrane Library. References were cross-checked. Pre- and postdiagnosis PA levels were assessed by MET. Usually, "high" PA was higher than 17 MET hour/week. Hazard ratios (HRs) for OS and CSS were calculated, with their 95% confidence interval. We used more conservative adjusted HRs, since variables of adjustment were similar between studies. When higher PA was associated with improved survival, HRs for detrimental events were set to <1. We used EasyMA software and fixed effect model whenever possible. Results. Seven studies (8056 participants) were included, representing 3762 men and 4256 women, 5210 colon and 1745 rectum cancers. Mean age was 67 years. HR CSS for postdiagnosis PA (higher PA versus lower) was 0.61 (0.44-0.86). The corresponding HR OS was 0.62 (0.54-0.71). HR CSS for prediagnosis PA was 0.75 (0.62-0.91). The corresponding HR OS was 0.74 (0.62-0.89). Conclusion. Higher PA predicted a better CSS. Sustained PA should be advised for CRC. OS also improved (reduced cardiovascular risk).
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http://dx.doi.org/10.1155/2013/340851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814048PMC
June 2014

[Assessment of nursing needs and risk management in geriatric oncology].

Soins Gerontol 2013 Jan-Feb(99):35-9

Service de SSR oncogériatrique, hôpital René-Muret (AP-HP), Sevran, France.

In France, the incidence and rate of mortality of cancer increase with age. For elderly patients suffering from cancer, the standard geriatric assessment, together with an oncological assessment aims to optimise the treatment. This geriatric oncology assessment enables the priorities to be identified and the cancer treatment to be adapted by anticipating the risks and organising the support care.
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April 2013

Refractory hypoglycemia controlled by sorafenib in solitary fibrous tumor.

J Clin Oncol 2013 Mar 22;31(9):e118-21. Epub 2013 Jan 22.

Service de Médecine Interne, Avicenne University Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France.

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http://dx.doi.org/10.1200/JCO.2011.40.7999DOI Listing
March 2013

Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients.

Dig Liver Dis 2013 Mar 24;45(3):245-50. Epub 2012 Oct 24.

Gastroenterology, Avicenne Hospital, APHP, Université Paris 13, Bobigny, France.

Objective: About 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients.

Design: Mismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres.

Results: 231 patients (median age: 81, range: 75-100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05-6.44; p=0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%).

Conclusion: deficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients.
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http://dx.doi.org/10.1016/j.dld.2012.09.013DOI Listing
March 2013

Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: a meta-analysis.

Crit Rev Oncol Hematol 2012 Dec 23;84(3):340-9. Epub 2012 Apr 23.

Department of Oncology, AP-HP, Avicenne Hospital, Paris-XIII University, 125 route de Stalingrad, 93009 Bobigny, France.

Background: In patients with advanced non-small cell lung cancer (NSCLC) aged more than 70 years, the benefit-to-risk ratio of doublet chemotherapy vs single-agent is not established.

Methods: We performed a meta-analysis (MA), with a PubMed query using keywords simultaneously (Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non-small cell lung/drug therapy). Abstracts from ASCO, WCLC, and ESMO proceedings were reviewed. Articles were also obtained by cross-checking references. Third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination with or without platinum were included. The efficacy outcomes were Overall Response Rate (ORR) and 1-Year Overall Survival (OS). We used EasyMA software and a random-effect model in case of heterogeneity.

Results: This MA comprised 10 studies including 2605 patients (mean age 74; 1866 men and 620 women; 654 stage IIIB and 1677 stage IV; 839 squamous cell cancers, 968 adenocarcinomas, 521 other pathological types). One-year OS (including the last trial by Abe) did not significantly improve for doublets compared with single-agents (HR 0.92; 95% Confidence Interval or CI: 0.82-1.03) whereas it improved significantly before inclusion of this last study, when the study by Quoix et al., the most favorable to doublets, was included. However, doublet chemotherapy significantly improved ORR after inclusion of Abe study (HR 1.51; 1.22-1.86; p<0.001). OS was not significantly improved, neither by doublets including platinum (HR 0.90, 0.70-1.16), nor by those without platinum (HR 0.94, 0.84-1.07). ORR, but not OS, was improved by doublets including a taxane (docetaxel and paclitaxel) (HR 1.72; 1.28-2.33) except for paclitaxel with a significant OS and ORR benefit. All-grade neutropenia thrombocytopenia and anemia were significantly more frequent with doublets than with single-agents (HR 1.26, 1.15-1.39; 1.75, 1.11-2.77 and 1.33, 1.17-1.52 respectively). Grade 3/4 thrombocytopenia and anemia but not neutropenia were significantly more frequent with doublets (HRs 2.13, 1.01-4.49 and 1.84, 1.29-2.63 respectively).

Conclusion: Compared with single-agents, doublets significantly improved ORR but not OS. They induced significantly more frequent thrombocytopenia and anemia. The benefit-to-risk ratio of doublets in advanced NSCLC might be more favorable than that of single agents, based on ORR but not OS.
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http://dx.doi.org/10.1016/j.critrevonc.2012.03.007DOI Listing
December 2012

Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma.

Neuro Oncol 2012 Apr 22;14(4):491-5. Epub 2012 Feb 22.

Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Service de Neurologie, France.

Approximately 10% of patients with non-small cell lung cancer (NSCLC) have brain metastases at the time of diagnosis. When surgical resection is not possible, whole brain radiotherapy is the standard of care, with a cerebral response rate of approximately 30%. We report our experience with an upfront association of carboplatin and pemetrexed (areas under the curve, 5 and 500 mg/m(2), respectively), every 3 weeks, in 30 patients presenting with newly diagnosed brain metastases and NSCLC. Cerebral MRIs were performed every 6-9 weeks. The radiologic response rates were assessed according to Response Evaluation Criteria in Solid Tumors. Overall survival was also determined. Twenty-six patients were evaluable for response, and the objective cerebral response rate (complete and partial response) in the intent-to-treat population was 40% (12 of 30 patients). Event-free survival was 31 weeks, and median overall survival was 39 weeks. The upfront association of carboplatin plus pemetrexed allows simultaneous treatment of cerebral and systemic disease in patients with NSCLC with newly diagnosed brain metastases and appears to be particularly interesting in terms of radiologic response and overall survival. Further clinical studies are warranted.
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http://dx.doi.org/10.1093/neuonc/nos004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309855PMC
April 2012

Comparison of FDG-PET/CT and MR with diffusion-weighted imaging for assessing peritoneal carcinomatosis from gastrointestinal malignancy.

Eur Radiol 2012 Jul 24;22(7):1479-87. Epub 2012 Feb 24.

Department of Nuclear Medicine, Université Paris 13, CHU Avicenne, 125 rue de Stalingrad, 93000, Bobigny, France.

Objectives: To assess the accuracy of FDG-PET/CT and MR with diffusion-weighted imaging (MR-DWI) for diagnosing peritoneal carcinomatosis (PC) from gastrointestinal malignancies.

Methods: Thirty consecutive patients referred for staging of gastrointestinal malignancy underwent FDG-PET/CT and MR-DWI in this retrospective study. Extent of PC was characterised by dividing the peritoneal cavity into three sites in each patient: right and left supramesocolic areas and inframesocolic level (total 90 sites). Presence of PC was confirmed either by surgery (18/30) or by follow-up (12/30).

Results: PC was confirmed in 19 patients (19/30). At a total of 90 sites, 27 showed proven PC. On a patient-based analysis, sensitivity, specificity, PPV, NPV and accuracy were respectively 84%, 73%, 84%, 73% and 80% for PET/CT and 84%, 82%, 89%, 75% and 83% for MR-DWI. On a site-based analysis, overall sensitivity and specificity of PET/CT (63%, 90%) and MR-DWI (74%, 97%) were not statistically different (P = 0.27). In the supramesocolic area, MR-DWI detected more sites involved than PET/CT (7/9 vs. 4/9). The sensitivities of PET and MR were lower for subcentimetre tumour implants (42%, 50%). Interobserver agreement was very good for PET/CT and good for MR-DWI.

Conclusions: FDG-PET/CT and MR-DWI showed similar high accuracy in diagnosing PC. Both techniques underestimated the real extent of PC because of decreased sensitivity for subcentimetre lesions.

Key Points: FDG-PET/CT and MR-DWI showed similar high accuracy for diagnosing peritoneal carcinomatosis. • In the supramesocolic area, MR-DWI could be more sensitive than PET/CT. • Both techniques showed lower sensitivity for subcentimetre lesions. • Interobserver agreement was very good for PET/CT and good for MR-DWI.
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http://dx.doi.org/10.1007/s00330-012-2397-2DOI Listing
July 2012

Cardiovascular toxicity of anti-angiogenic drugs.

Target Oncol 2011 Dec 25;6(4):197-202. Epub 2011 Nov 25.

Department of Medical Oncology, France and Paris-XIII University, Bobighy.

Anti-angiogenic targeted therapies are now major tools in the management of solid tumors. Briefly, one can distinguish between monoclonal antibodies such as bevacizumab directed against vascular endothelial growth factor (VEGF) and small molecules such as those targeted against receptors with tyrosine-kinase activity. Soon after they were marketed, these drugs showed cardiovascular toxicities, such as hypertension, left ventricular systolic dysfunction, heart failure and conduction abnormalities. The most frequent cardiovascular side effect of targeted therapies is hypertension, but the most life-threatening is QT prolongation with its risk of torsade de pointe and sudden cardiac death. Since the incidence of different types of cardiovascular side effects following targeted therapies varies across studies-and despite the fact that several meta-analyses attempted to summarize available information-those side effects are still not well identified. In addition, their reversibility is not precisely known. This review aims to present and discuss the various cardiovascular toxicities of anti-angiogenic targeted therapies for cancer.
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http://dx.doi.org/10.1007/s11523-011-0204-7DOI Listing
December 2011

Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study.

Dis Colon Rectum 2011 Aug;54(8):930-8

Department of GI Oncology and Laboratory of Clinical Investigation 4393, Universite Paris-Est Créteil (UPEC), Créteil, France.

Background: Whether patients with stage IV colon cancer and unresectable distant metastases should be managed by primary colectomy followed by chemotherapy or immediate chemotherapy without resection of the primary tumor is still controversial.

Objective: This study aimed to evaluate predictive factors associated with survival in patients with stage IV colon cancer and unresectable distant metastases.

Design: This large retrospective multicentric study included 6 academic hospitals.

Settings: This study was conducted at 6 Paris University Hospitals (Assistance Publique-Hôpitaux de Paris; Saint Antoine, Henri Mondor, Ambroise Paré, Hôpital Europeen Gorges Pompidou, Bichat, and Avicenne).

Patients: Between 1998 and 2007, 208 patients with good performance status and stage IV colon cancer with unresectable distant metastases received chemotherapy, either as initial management or after primary tumor resection.

Main Outcome Measures: Survival was estimated by use of the Kaplan-Meier method. Factors associated with survival were tested by means of a log-rank test. Results were expressed as median values with 95% confidence intervals. Factors independently related to survival were tested using a Cox regression model adjusted for a propensity score.

Results: Of the 208 patients, 85 underwent colectomy before chemotherapy, whereas 123 were treated with use of primary chemotherapy with or without biotherapy. At univariate analysis, the following factors were significantly associated with survival: primary colectomy (P = .031), secondary curative surgery (P < .001), well-differentiated primary tumor (P < .001), exclusive liver metastases (P < .027), absence of need for colonic stent (P = .009), and addition of antiangiogenic (P = .001) or anti-epidermal growth factor receptor (P = .013) drugs to chemotherapy. After Cox multivariate analysis and after adjusting for the propensity score, all of these factors, with the exception of two, colonic stent and anti-epidermal growth factor receptor drug, were found to be independently associated with overall survival.

Limitation: This study was limited by its retrospective nature.

Conclusions: In a selected population of patients with colon cancer and unresectable synchronous distant metastases, immediate colectomy followed by chemotherapy in association with targeted therapy was associated with longer overall survival. This strategy appears to be the most appropriate, especially for those with good performance status, well-differentiated tumors, and synchronous liver metastases only.
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http://dx.doi.org/10.1097/DCR.0b013e31821cced0DOI Listing
August 2011

Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis.

Eur J Cancer 2010 Apr;46(6):1049-55

AP-HP, Department of Oncology, Avicenne Hospital, 125 route de Stalingrad, 93009 Bobigny, France.

Background: In stage III colorectal cancer (CRC), adjuvant chemotherapy (CT) is usually prescribed within two months after curative surgery. Whether or not delaying initiation of CT affects survival is still debated.

Material And Methods: We performed a meta-analysis (MA) of all published studies (full papers or abstracts) comparing delayed CT with standard care. Studies were obtained from a PubMed query (keywords: CRC, adjuvant treatment, delay of CT), a review (Chau et al., 2006), cross-checking references and abstracts from the proceedings of ASCO, ASCO GI and WCGI annual meetings. We chose a cutoff delay of 8 weeks. Risk Ratios (RRs) were calculated from the recorded events (deaths, relapses). We used EasyMA software (fixed-effect model).

Results: Fourteen studies (including four abstracts) were identified (17,645 patients; 5,952 males, 5,151 females, mean age 70 years). Of these, three could not be statistically analysed and three used another cutoff (4, 5 or 6 weeks), leaving 8 studies for main MA (13,158 patients; 3,932 males, 3,644 females, 5,942 missing data; 5,576 colon cancers, 6,677 rectal, 1,265 missing data). Delaying CT more than 8 weeks was associated to worse Overall Survival (OS) (RR: 1.20; 95% Confidence Interval (CI) 1.15-1.26). In the MA including all studies whatever their cutoff, longer delay was similarly associated to a worse OS but not a worse Relapse-Free Survival (RFS) (five studies).

Conclusion: Adjuvant chemotherapy should be started within 8 weeks after surgery. Delaying the initiation of adjuvant CT for more than 8 weeks after surgery significantly decreased OS but not RFS. This discrepancy might be due to factors not directly related to cancer (post-operative complications, social status) or to a more accurate appraisal of death.
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http://dx.doi.org/10.1016/j.ejca.2010.01.020DOI Listing
April 2010

Duration of adjuvant chemotherapy for patients with non-metastatic colorectal cancer.

Cochrane Database Syst Rev 2010 Jan 20(1):CD007046. Epub 2010 Jan 20.

Oncology, Hospital Avicenne, 125 Rue de Stalingrad, Bobigny, France, 93009.

Background: Surgery of primary tumour is the backbone of colorectal cancer treatment (CRC). But in stage III cancer, metastatic or local relapse is often observed (50%). So, adjuvant treatment is always considered in this setting. The best treatment duration of hypothetic disease is not easy to define. Adjuvant chemotherapy for CRC actually lasts 6 months. The choice of optimal duration is based upon old studies using 5-fluorouracil (5FU). During the last ten years, results of major randomized controlled studies (RCTs) comparing different durations of treatments and different schedules in adjuvant setting were published. Several studies compared a 6-month chemotherapy with a longer treatment. Conversely, a single study by Chau et al compared a 6 month chemotherapy with continuous treatment lasting 3 months. But the optimal duration of these chemotherapies could be challenged. Even though the optimal duration of chemotherapy in CRC is a major issue, it has never been answered adequately.

Objectives: To evaluate the optimal duration of adjuvant treatment, we performed a meta-analysis of all RCTs comparing two durations of adjuvant treatment, 6 months versus 9 to 12 months.

Search Strategy: Publications were identified from PubMed (February 28th, 2009), Embase, and the Cochrane Database of Clinical Controlled Trials (CENTRAL) in the Cochrane Library 2009 issue 1. Reviews and books were also scrutinized. Abstracts were reviewed from ASCO annual meetings proceedings from 1998 to 2009.

Selection Criteria: Patients with surgically resected colorectal cancer with high risk of recurrence.

Data Collection And Analysis: Several RCTs compared shorter versus longer durations of chemotherapy, 6 studies for overall survival (OS) and 7 studies for relapse free survival (RFS), for a total of 10326 patients, mean age 63.1 years, including 9826 colon and 500 rectum cancers.

Main Results: Treatments were always based on 5-FU. Two studies were excluded, an epidemiological study and a study comparing continuous treatment during 3 months with conventional chemotherapy during 6 months. The later because it compared 2 durations less than or equal to 6 months. Shorter duration of chemotherapy (3-6 months) compared with longer duration (9-12 months) was not associated to poorer RFS (RR =0.96, 95% CI : 0.90-1.02) and OS (RR = 0.96 ; 95% CI : 0.91-1.02).

Authors' Conclusions: The present meta-analysis confirmed that adjuvant chemotherapy of CRC should not last for more than 6 months. Prolonged duration would result in lower benefit to risk ratio. However, the results do not make it possible to favour either 3 or 6 month durations. They should help design a future RCT comparing different durations of continuous treatment.
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http://dx.doi.org/10.1002/14651858.CD007046.pub2DOI Listing
January 2010

Postirradiation sarcoma: clinicopathologic features and role of chemotherapy in the treatment strategy.

Sarcoma 2009 ;2009:764379

Department of Medical Oncology, Curie Institut, 75005 Paris, France.

Purpose. An analysis of the clinicopathologic features and treatment of patients was performed to guide evaluation and management of postirradiation sarcoma. Patients and Methods. Between 1994 and 2001, 25 patients with postirradiation sarcoma were treated in one center with different chemotherapy, mainly in neoadjuvant setting (19). Tumors for which these patients received radiotherapy initially were mainly breast carcinoma (for 15 patients). The postirradiation sarcomas were of different histopathologic forms, most frequently osteosarcoma, leiomyosarcoma, and angiosarcoma. Results. Of the 25 patients, 19 were initially treated with chemotherapy. Nine of 19 pretreated patients achieved clinical partial response (RP = 47%). Leiomyosarcomas were good responders (3/4) and undifferentiated sarcoma (3/5). Responders were more often treated with MAID (6/8). Eight of the 9 responders underwent surgery. Two patients achieved complete histological response. Seven of the 9 good responders are alive with a median follow up of 24 months. For all treated patients, median follow up 24 months (6-84 months), overall survival and disease free survival were, respectively, 17/25 (68%), and 14/25 (56%). Conclusion. From our data, postirradiation sarcoma should not be managed differently from primary sarcoma. Chemotherapy has to be included in the treatment plan of postirradiation sarcoma, in future studies.
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http://dx.doi.org/10.1155/2009/764379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790134PMC
July 2011