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Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF). In this multicenter randomized double-blind placebo-controlled phase III study ( ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization. Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, − 2.9; P, − 2.5 points, p = 0.756) and relative decrease (A, − 17%; P, − 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470). The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile.

Backround Radiolabeled OTSA101, a monoclonal antibody targeting synovial sarcoma (SS) developed by OncoTherapy Science, was used to treat relapsing SS metastases following a theranostic procedure: in case of significant 111In-OTSA101 tumor uptake and favorable biodistribution, patient was randomly treated with 370/1110 MBq 90Y-OTSA101. Monte Carlo-based 3D dosimetry integrating time-activity curves in VOI was performed on 111In-OTSA101 repeated SPECT/CT. Estimated absorbed doses (AD) in normal tissues were compared to biological side effects and to the admitted maximal tolerated absorbed dose (MTD) in normal organs. Results in the tumors were also compared to disease evolution. Results Biodistribution and tracer quantification were analyzed on repeated SPECT/CT acquisitions performed after injection of 111In-OTSA101 in 19/20 included patients. SPECT images were warped to a common coordinates system with deformable registration. Volumes of interest (VOI) for various lesions and normal tissues were drawn on the first CT acquisition and reported to all the SPECT images. Tracer quantification and residence time of 111In-OTSA101 in VOI were used to evaluate the estimated absorbed doses per MBq of 90Y-OTSA101 by means of Monte Carlo simulations (GATE). A visual scale analysis was applied to assess tumor uptake (grades 0 to 4) and results were compared to the automated quantification. Results were then compared to biological side effects reported in the selected patients treated with 90Y-OTSA101 but also to disease response to treatment. After screening, 8/20 patients were treated with 370 or 1110 MBq 90Y-OTSA101. All demonstrated medullary toxicity, only one presented with transient grade 3 liver toxicity due to disease progression, and two patients presented with transient grade 1 renal toxicity. Median absorbed doses were the highest in the liver (median, 0.64 cGy/MBq; [0.27 −1.07]) being far lower than the 20 Gy liver MTD, and the lowest in bone marrow (median, 0.09 cGy/MBq; [0.02 −0.18]) being closer to the 2 Gy bone marrow MTD. Most of the patients demonstrated progressive disease on RECIST criteria during patient follow-up. 111In-OTSA101 tumors tracer uptake visually appeared highly heterogeneous in inter- and intra-patient analyses, independently of tumor sizes, with variable kinetics. The majority of visual grades corresponded to the automated computed ones. Estimated absorbed doses in the 95 supra-centimetric selected lesions ranged from 0.01 to 0.71 cGy per injected MBq (median, 0.22 cGy/MBq). The maximal tumor AD obtained was 11.5 Gy. Conclusions 3D dosimetry results can explain the observed toxicity and tumors response. Despite an intense visual 111In-OTSA101 liver uptake, liver toxicity was not the dose limiting factor conversely to bone marrow toxicity. Even though tumors 111In-OTSA101 avidity was visually obvious for treated patients, the low estimated tumors AD obtained by 3D dosimetry explain the lack of tumor response.

Purpose Surgical resection plus adjuvant platinum-based chemotherapy is considered standard care for stage II to III non–small-cell lung cancer (NSCLC), but its efficacy is limited, and it involves toxic risks, justifying patient-tailored treatment. Excision repair cross-complementation group 1 (ERCC1) was shown to predict cisplatin-based chemotherapy response; EGFR mutations were predictive of epidermal growth factor receptor inhibition response. Patients and Methods This prospective randomized phase II trial enrolled 150 patients with completely resected non–squamous cell stage II or IIIA (non-N2) tumors. Patients in the control arm (n = 74) were treated with four standard-dose courses of cisplatin plus pemetrexed (CP). In the customized treatment arm (n = 76), patients with activated EGFR mutations received erlotinib 150 mg for 1 year; ERCC1-negative patients received four CP courses, whereas ERCC1-positive patients underwent follow-up. The trial sought to demonstrate the feasibility of customized adjuvant chemotherapy based on timely biomarker analysis within a 2-month postsurgery delay. Secondary objectives were tolerability, compliance with adjuvant therapy, and biomarker distribution. Results In arm A, all patients received CP; in arm B, seven received erlotinib, 53 were administered CP, and 16 underwent follow-up. Median erlotinib exposure was 344 days. Of the 127 patients allocated to CP, 82% received four cycles with good tolerability. The overall success rate of the trial (ie, percentage of patients with complete biomarker status able to start adjuvant treatment within 2 months of surgery) was 80%. Conclusion The primary end point of the trial was met, demonstrating the feasibility of a national biology-driven trial in the adjuvant NSCLC setting. Nevertheless, the phase III part was canceled because of the unreliability of the ERCC1 immunohistochemical readouts.

A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2 weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600 mg) at Day 1 (given alone) and Day 15 (the day of the 7.5 mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/F, mean value of 0.60 L/h) presented an inter-individual variability of 40 %, and an inter-occasion of 27 %. A modest but statistically significant decrease in CL/F was observed from Day 1 to Day 15 (-16.4, 95 % confidence interval of -8.5 to -27.2 %). However, trough pazopanib concentrations observed at Day 16 (24 h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600 mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors.

BACKGROUND Personalized anti-tumoral therapies may currently be proposed on the basis of immuno-histochemistry, but also next-generation sequencing and comparative genomic hybridization. ProfiLER trial explored the feasibility, efficacy and the impact of molecular profiling for patients with solid or hematological advanced cancers including brain tumors. MATERIAL AND METHODS Patients with primary brain tumors, pre-treated with at least one line of anti-cancer treatment, could be included in this multicentric prospective trial. A molecular profile (next-generation sequencing and comparative genomic hydridization) was established on fresh or archived sample. Weekly molecular tumor board analysed results to propose as far as possible a molecular targeted therapy. RESULTS between February 2013 and December 2015, 141 patients with primary brain tumor were enrolled. One hundred five samples were further analyzed as 30 samples were excluded, and 6 are on-going. The rate of screen failure was 16/33 for stereotactic biopsy (49%) versus 11/104 (11%) for removal. The main representative histologic type of tumors were glioblastoma (n=46, 43,8%), low grade glioma (n=26, 24,8%), high grade glioma (n=12, 11,4%) and atypical and anaplastic meningioma (n=8, 7,6%). Median delay between the diagnostic of the primitive tumor and the inclusion in ProfiLER study was 2.7 years (0.2 - 29 years). Median delay between the consent and the results of the multidisciplinary meeting was 2.8 months (1–7.1 months). Forty-three patients (41%) presented at least one “druggable molecular alteration”. The most frequently altered genes were CDKN2A (n=18, 29%), EGFR (n=12, 20%), PDGFRa (n=8, 13%), PTEN (n=8, 13%), CDK4 (n=7, 11%), KIT (n=6, 10%), PIK3CA (n=5, 8%), MDM2 (n=3, 5%). Sixteen patients could not have a proposition of specific treatment due to death before MBT (n=5, 31.3%), lack of available clinical trials (n=9, 56%), or ambiguous results (n=2, 12.5%). Among the 27 patients (26%) for whom a specific therapy has been proposed, only six patients ultimately received a medical targeted therapy (everolimus n=3, erlotinib n=1, ruloxitinib n=1, sorafenib n=1). Four patients discontinued the treatment for toxicity, the 2 others for clinical progression. CONCLUSION routine high-throughput sequencing is feasible for brain tumors but delays should be reduced to be able to propose targeted therapies to patients fit enough to benefit from experimental treatment. Macroscopic surgery is the best way to obtain workable samples. Specific panel genes for neurologic tumors should be developed, as well as change of practices concerning exclusion criteria in clinical trials.

e18079 Background: Internationally recognised criteria to evaluate tumour response, such as Response Evaluation Criteria In Solid Tumors (RECIST) and iRECIST (for immunotherapeutics) are not widely used in clinical practice. The main reason is that communications amongst health professionals are insufficiently standardised. To this purpose, ON’COHUB (MIRIO in France), a newly developed tool, automatically streamlines interactions between oncologists and radiologists to optimise and facilitate response evaluation according to the standard criteria. This study aims to identify the benefits in terms of user satisfaction and to provide preliminary data for the standardisation of the tool. Methods: Five oncologists, 3 radiologists, 1 clinical research associate and 1 clinical project officer used ON’COHUB to assess patients’ tumour responses according to RECIST, in an anti-cancer center, over five months. An oncologist compared patients’ regular radiology reports (n = 110) and ON’COHUB’s reports (n = 106), using the following report quality indicators: information on the patient’s context, target and non-target lesions , baseline, NADIR, and overall evaluation. Then a questionnaire on the user’s satisfaction was administered. Two-tailed chi-square tests were performed to compare patients’ regular radiology reports and ON’COHUB’s reports. Results: ON’COHUB was reported to significantly improve the following quality indicators compared to regular reports: presence of the treatment (99% vs 42%; p < 0,001), follow-up criteria (98% vs 5%; p < 0,001); target lesion and location (100% vs 75%; p < 0,001), size of target lesions (99% vs 67%; p < 0,001), value and date of the baseline (100% vs 0% and 4%, respectively; p < 0,001 for both), value of the baseline lesion by lesion (99% vs 4%; p < 0,001), value and date of the Nadir (97% vs 0%; p < 0,001), global response according to RECIST (100% vs 17%; p < 0,001), value of target lesions response (80% vs 20%; p < 0,001), referential for RECIST calculation (98% vs 2% p < 0,001).Finally, 9 out of the 10 users declared that they would use ON’COHUB on a daily basis. Conclusions: These preliminary data suggest that ON’COHUB may have a positive impact on the quality of the treatment response evaluation in clinical trials and in routine use. These results will be confirmed with the deployment of the interoperability with IT hospital System.

2579 Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( > 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( > 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after > 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.

The aim of this study was to assess the feasibility, safety, and accuracy of HIFU ablation in patients with liver metastases in a prospective phase II trial. The transducer has a toroidal shape (diameter: 70 mm, radius of curvature: 70 mm) and was divided into 32 ring-shaped emitters operating at 2.5 MHz. Thirty-one patients were included. HIFU ablations were created to ablate metastases (up to 30 mm in diameter) with safety margins in all directions. The use of a toroidal transducer enables an ablation rate (10 cc min-1) significantly higher than spherical transducers. Therefore, using electronic focusing of the beam, it was possible to treat all metastases with safety margin without the need to displace the device between HIFU exposures. The exposure time varied from 40 s to 370 s according to the diameter of the metastases to be treated. The dimensions of these HIFU ablations were a diameter of 48 ± 4.9 mm and a long axis of 45 ± 3.4 mm. No damage occurred to neighboring tissues. This study is the first clinical use of intra-operative HIFU in patients with liver metastases.The aim of this study was to assess the feasibility, safety, and accuracy of HIFU ablation in patients with liver metastases in a prospective phase II trial. The transducer has a toroidal shape (diameter: 70 mm, radius of curvature: 70 mm) and was divided into 32 ring-shaped emitters operating at 2.5 MHz. Thirty-one patients were included. HIFU ablations were created to ablate metastases (up to 30 mm in diameter) with safety margins in all directions. The use of a toroidal transducer enables an ablation rate (10 cc min-1) significantly higher than spherical transducers. Therefore, using electronic focusing of the beam, it was possible to treat all metastases with safety margin without the need to displace the device between HIFU exposures. The exposure time varied from 40 s to 370 s according to the diameter of the metastases to be treated. The dimensions of these HIFU ablations were a diameter of 48 ± 4.9 mm and a long axis of 45 ± 3.4 mm. No damage occurred to neighboring tissues. This study is the firs...

PurposeThe currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme.ParticipantsAll consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually.Finding to dateWith a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort.Future plansThese real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings.Trial registration numberNCT03275311; Pre-results.

Introduction: high dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is an effective treatment in relapsed follicular lymphoma (FL). Alternative regimens including bendamustine based conditioning (BeEAM) had been developed to improve lymphoma outcome. Visani et al. showed in a phase I/II for relapsed aggressive lymphomas and relapsed Hodgkin lymphomas that bendamustine used at a dose of 200mg/m2, 2 days in combination with cytarabine (400 mg/m2, day-5 to day-2), etoposide (200 mg/m2, day-5 to day-2) and melphalan (140 mg/m2, day-1) was well tolerated with promising efficacy results. We designed a single arm, multicenter, phase II study for first and second chemosensitive relapses in FL patients (pts) evaluating this conditioning regimen. Methods: The primary endpoint is the efficacy of BeEAM by measuring the 2-year event-free survival (2-year EFS) rate defines by relapse, progression, death from any cause and initiation of a new therapy. The hypothesis was the improvement of 2-year EFS rate from 70% (H0) to 85% (H1). Based on a Fleming-A'Hern single-stage design, 50 pts are needed. Secondary endpoints are: overall response rate (ORR) at day 100 according to 2007 Cheson criteria; progression-free survival (PFS); overall survival (OS) and safety profile of BeEAM. Main eligible criteria are: histologically confirmed FL relapsed (WHO grade 1, 2, 3a); aged 18-65 years; first or second chemosensitive relapses after salvage immunochemotherapy based on 2007 Cheson criteria with a complete (CR) or a partial response (PR) before the BeEAM; eligibility for ASCT; signed informed consent. This trial was funded by the French government PHRC program 2012. Results: Twenty-one pts were included between July 2014 and November 2016 in 7 LYSA centers. One patient did not receive the treatment. The final analysis was based on 20 pts. Inclusion were performed for 16 (80%) and 3 (15%) pts at 1st and 2nd relapses, respectively. One patient (5%) was included at 3rd relapse and is considered as protocol minor deviation. The median time between the initial diagnostic and the 1st relapse was 3.6 years (0.7-12.9). In first-line therapy, 17/20 pts (85%) were treated with immunochemotherapy. At the relapse allowing inclusion, the FLIPI score were 0-1, 2, ≥3 for 6 (32%), 7 (36%), 6 (32%) pts, respectively. Salvage treatments were rituximab (R) associated with, dexamethasone, cytarabine, and platin in 19 pts and R-CHOP in one patient. The median age at inclusion was 57 years (range, 39-63); 16 (80%) and 4 (20%) pts were in CR and PR before BeEAM. After 18 included pts, the protocol was amended due to unexpected toxicities especially two hepatic veino-occlusive diseases (VOD), leading to the reduction of bendamustine dosage. Finally, 17 and 3 pts were respectively treated at 200mg/m2, 2 days and 160mg/m2, 2 days. The median time for neutrophil>0.5 G/L and platelet recoveries>20 G/L were 7.5 (0-11) and 7 (2-18) days. Patients received a median of 4 (0-12) packed red blood cell units and 6 (3-21) platelet units until J100. The median duration of hospital stay duration was 27 days (20-50). Response evaluation at J100 showed 19 CR pts and one patient in progressive disease. The ORR was 95.0% (95%CI, 75.1-99.9). Six pts progressed with two deaths of the FL (Figure 1A). With a median follow-up of 31 months (16-42), the 2-year EFS rate was 59.6% (95%CI, 35.1-77.4) but two events correspond to unplanned rituximab maintenance in two CR pts (Figure 1B). The PFS and OS rates were 69.6% (95%CI, 44.5-85.1) and 90% (95%CI, 65.6-97.4), respectively (Figure 1C). Fifteen pts (75%) had infectious complications until J100 that needed treatments for more than 7 days. Grade ≥3 toxicities were infections (N=18, 90%), gastrointestinal disorders (N=14, 70%), mucositis (N=12, 60%); atrial flutter (N=1, 5%); acute renal failure (N=2, 10%); HHV6 reactivation (N=3, 15%). In total, 29 serious adverse events (SAE) were declared for 16 pts. Two pts experienced VOD classified as unexpected SAE; one of them needed a hepatic transplantation. No patient presented toxic death. Conclusions: the prospective evaluation of BeEAM conditioning in FL pts with a chemosensitive relapses showed excessive toxicities especially infectious complications, cases of VOD leading to premature termination of the trial. Based on the 20 treated pts, the outcome seems not improve with the use of BeEAM. Our study does not encourage the use of BeEAM conditioning in relapsed FL pts. Disclosures Ghesquieres: Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Le Bras:Amgen: Consultancy. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Cartron:Celgene: Consultancy, Honoraria; Gilead Sciences: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria.

International audience; BACKGROUND: Cancer patients with CD4 lymphopenia have an increased risk of severe toxicity after administration of cytotoxic chemotherapy. The impact of CD4 lymphopenia on long term overall survival (OS) of cancer patients was explored in this work. PATIENTS AND METHODS: The first prospective series (test series) included 219 patients with solid tumours, lymphomas or myelomas receiving chemotherapy within an oncology department in 1999 and 2000. A phenotypic analysis of lymphocyte subsets by flow cytometry was performed before chemotherapy on day 1. The prognostic value of total, CD4, CD8 and CD56 lymphocyte count for OS was tested in a multivariate analysis. The prognostic value of low CD4 counts was then tested in a validation series of 269 patients with metastatic solid tumours in second line treatment included in a prospective observational study in the Centre Leon Berard. RESULTS: In the test series, all patients with metastatic cancers and CD4 lymphopenia ≤ 200/μL (12% of metastatic patients) died within 18 months with a median OS of 5.9 months. CD4 count was an independent prognostic factor for OS and PFS in multivariate analysis. In the validation series, 83 (30%) of patients had CD4 count ≤ 200/μL: their median overall survival was 3.9 months with an 18-month survival rate of 6%. CD4 count was also an independent prognostic factor for overall survival in this series. CONCLUSIONS: CD4 lymphopenia

Use of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) filgrastim accelerates neutrophil recovery following myelosuppressive chemotherapy. Since filgrastim requires multiple daily administrations, forms of rhG-CSF with a longer half life, including pegfilgrastim, have been developed. Pegfilgrastim is safe and effective in supporting neutrophil recovery and reducing febrile neutropenia after conventional chemotherapy. Pegfilgrastim has also been successfully used to support patients undergoing peripheral blood stem cell (PBSC) transplantation for haematological malignancies. To our knowledge, no cost-effectiveness analysis (CEA) of pegfilgrastim in this setting has been published yet.We undertook a CEA to compare a single injection of pegfilgrastim versus repeated administrations of filgrastim in patients who had undergone PBSC transplantation for lymphoma or myeloma. The CEA was set in France and covered a period of 100 ± 10 days from transplant.The CEA was designed as part of an open-label, multicentre, randomized phase II trial. Costs were assessed from the hospital's point of view and are expressed in 2009 euros. Costs computation focused on inpatient, outpatient, and home care. Costs in the two arms of the study were compared using the Mann-Whitney test. When differences were statistically significant, multiple regression analyses were performed in order to identify cost drivers. Incremental cost-effectiveness ratios (ICER) were calculated for the major endpoints of the trial; i.e., duration of febrile neutropenia (absolute neutrophil count [ANC]0.5 × 10(9)/L and temperature ≥38 °C), duration of neutropenia (ANC1.0 × 10(9)/L and ANC0.5 × 10(9)/L), duration of thrombopenia (platelets50 × 10(9)/L and20 × 10(9)/L), and days with a temperature ≥38 °C). Uncertainty around the ICER was captured by a probabilistic analysis using a non-parametric bootstrap method.151 patients were enrolled at ten French centres from October 2008 to September 2009. The mean total cost in the pegfilgrastim arm of the study (n = 74) waseuro25,024 (SD 9,945). That in the filgrastim arm (n = 76) waseuro28,700 (SD 20,597). Pegfilgrastim strictly dominated filgrastim for days of febrile neutropenia avoided, days of neutropenia (ANC1.0 × 10(9)/L) avoided, days of thrombopenia (platelets20 × 10(9)/L) avoided, and days with temperature ≥38 °C) avoided. Pegfilgrastim was less costly and less effective than filgrastim for the number of days with ANC0.5 × 10(9)/L avoided and the number of days with platelets50.0 × 10(9)/L avoided. Taking uncertainty into account, the probabilities that pegfilgrastim strictly dominated filgrastim were 67 % for febrile neutropenia, 86 % for neutropenia (ANC1.0 × 10(9)/L), 59 % for thrombopenia (platelets20 × 10(9)/L), 86 % for temperature ≥38 °C, 32 % for neutropenia (ANC0.5 × 10(9)/L), and 43 % for thrombopenia (platelets50 × 10(9)/L). Conversely, the probability that filgrastim strictly dominated pegfilgrastim for neutropenia (ANC0.5 × 10(9)/L) is 5 %.This study found no evidence that the use of pegfilgrastim is associated with greater cost in lymphoma and myeloma patients after high-dose chemotherapy and PBSC transplantation.

Purpose This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non–small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy. Patients and Methods Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m2 days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m2 once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS). Results PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events. Conclusion Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

Présenté par Lionel Perrier; International audience

International audience; BACKGROUND: The added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study. METHODS: Of the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status. RESULTS: Mutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) \textless2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557-558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176). CONCLUSIONS: In GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS

Purpose This cost analysis aimed to prospectively assess differences in costs between TomoTherapy and volumetric modulated arc therapy (VMAT) in patients with head and neck cancer. Methods and Materials Economic data were gathered from a multicenter study. However, randomization was not possible due to the availability of equipment. Costs were calculated using the microcosting technique from the hospital's perspective (in 2013 euros), and the time horizon was radiation therapy. Only resources that entered the hospital production process and which were likely to vary between the strategies being compared were considered. Acute adverse events observed within the time horizon were also assessed. Results The cost analysis was based on a total of 173 patient treatments given between 2010 and 2012 in 14 French cancer centers: 73 patients were treated with TomoTherapy, 92 with VMAT RapidArc, and 8 with VMAT SmartArc. Estimated costs of SmartArc were removed from the comparison due to the small sample size. The mean ± SD cost per patient of the treatment planning phase was €314 (±€214) for TomoTherapy and €511 (±€590) for RapidArc. Mean costs ± SD per patient of irradiation reached €3144 (±€565) for TomoTherapy and €1350 (±€299) for RapidArc. The most sensitive parameter of irradiation was the annual operating time of accelerators. Ninety-five percent confidence intervals for the mean costs of irradiation were €3016 to €3272 for TomoTherapy and €1281 to €1408 for RapidArc. The number of acute adverse events during radiation therapy was not significantly different between strategies. Conclusions TomoTherapy appeared to be more expensive than RapidArc mainly due to the higher price of the accelerator, the higher costs of maintenance, and the longer duration of treatment sessions. Because strategies were not significantly different in clinical effect, RapidArc appeared to be the strategy to be recommended at this stage of knowledge.

A better understanding of the dynamics of molecular changes occurring during the early stages of oral tumorigenesis may help refine prevention and treatment strategies. We generated genome-wide expression profiles of microdissected normal mucosa, hyperplasia, dysplasia and tumors derived from the 4-NQO mouse model of oral tumorigenesis. Genes differentially expressed between tumor and normal mucosa defined the "tumor gene set" (TGS), including 4 non-overlapping gene subsets that characterize the dynamics of gene expression changes through different stages of disease progression. The majority of gene expression changes occurred early or progressively. The relevance of these mouse gene sets to human disease was tested in multiple datasets including the TCGA and the Genomics of Drug Sensitivity in Cancer project. The TGS was able to discriminate oral squamous cell carcinoma (OSCC) from normal oral mucosa in 3 independent datasets. The OSCC samples enriched in the mouse TGS displayed high frequency of CASP8 mutations, 11q13.3 amplifications and low frequency of PIK3CA mutations. Early changes observed in the 4-NQO model were associated with a trend toward a shorter oral cancer-free survival in patients with oral preneoplasia that was not seen in multivariate analysis. Progressive changes observed in the 4-NQO model were associated with an increased sensitivity to 4 different MEK inhibitors in a panel of 51 squamous cell carcinoma cell lines of the areodigestive tract. In conclusion, the dynamics of molecular changes in the 4-NQO model reveal that MEK inhibition may be relevant to prevention and treatment of a specific molecularly-defined subgroup of OSCC.

To report the long-term results of the French Genitourinary Study Group (GETUG)-01 study in terms of event-free survival (EFS) and overall survival (OS) and assess the potential interaction between hormonotherapy and pelvic nodes irradiation.Between December 1998 and June 2004, 446 patients with T1b-T3, N0pNx, M0 prostate carcinoma were randomly assigned to either pelvic nodes and prostate or prostate-only radiation therapy. Patients were stratified into 2 groups: "low risk" (T1-T2 and Gleason score 6 and prostate-specific antigen3× the upper normal limit of the laboratory) (92 patients) versus "high risk" (T3 or Gleason score6 or prostate-specific antigen3× the upper normal limit of the laboratory). Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for high-risk patients. Radiation therapy was delivered with a 3-dimensional conformal technique, using a 4-field technique for the pelvic volume (46 Gy). The total dose recommended to the prostate moved from 66 Gy to 70 Gy during the course of the study. Criteria for EFS included biologic prostate-specific antigen recurrences and/or a local or metastatic progression.With a median follow-up of 11.4 years, the 10-year OS and EFS were similar in the 2 treatment arms. A higher but nonsignificant EFS was observed in the low-risk subgroup in favor of pelvic nodes radiation therapy (77.2% vs 62.5%; P=.18). A post hoc subgroup analysis showed a significant benefit of pelvic irradiation when the risk of lymph node involvement was15% (Roach formula). This benefit seemed to be limited to patients who did not receive hormonal therapy.Pelvic nodes irradiation did not statistically improve EFS or OS in the whole population but may be beneficial in selected low- and intermediate-risk prostate cancer patients treated with exclusive radiation therapy.

Introduction Le pemetrexed (pem) est indique en association au cisplatine (cis) chez les patients (pts) atteints de mesotheliome pleural malin (MPM) et naifs de chimiotherapie, en 1 re ligne du cancer bronchique non a petites cellules non epidermoide (CBNPCne) avance et en monotherapie pour la maintenance et le traitement en 2 e ligne du CBNPCne. L’objectif etait de decrire l’usage du pem chez les pts atteints de CBNPCne ou de MPM dans la pratique clinique courante en France. Methodes Dans cette etude observationnelle retrospective multicentrique chez des adultes initiant une nouvelle ligne de traitement par pem en 2012–2013, les centres et pts ont ete selectionnes au hasard pour obtenir un echantillon representatif. L’usage de pem a ete decrit en termes de caracteristiques des pts, usage/administration de pem, hospitalisations et evenements indesirables lies. Les facteurs pronostiques associes a l’usage des sels de platine carboplatine (cb)/cis ont ete etudies dans la cohorte CBNPCne. Les criteres analyses pour evaluer la concordance entre la prescription de pem et ses indications approuvees par l’EMA etaient : histologie, stade de la maladie, ligne de traitement et protocole therapeutique. Resultats Sur 535 pts, 86,5 % (463/535) ont recu le pem conformement a ses indications approuvees par l’UE ; 97,6 % respectaient les criteres histologiques, 94,6 % le stade de la maladie, 93,5 % la ligne de traitement et 54,4 % le protocole therapeutique. Le pem a ete utilise pour le CBNPCne dans 89,7 % des cas, principalement en 1 re ligne (78,7 %) ou il a ete associe au cb chez 37,2 % des pts ; cette prescription etait significativement associee a des caracteristiques de mauvais pronostic (âge ≥ 70 ans, indice de performance ≥ 2 et presence de comorbidites). Les frequences des transfusions (19,1 % des pts), des ajustements et des arrets de traitement etaient similaires a celles des etudes controlees randomisees. Les evenements indesirables attribues au pem ont ete rapportes chez 22,8 % des pts. Les limites cles de l’etude comprennent d’eventuels biais dans les reponses et la sous-representation du traitement en 2 e ligne et de la maintenance. Conclusion En France, au moment du deroulement de l’etude, le pem etait principalement utilise en 1 re ligne dans le CBNPCne et le MPM. Les prescriptions etaient conformes a ces indications pour la majorite des pts inclus dans l’etude. Cb a ete prescrit comme une alternative au cis, principalement en presence de facteurs de mauvais pronostic.

Background In the evolution of metastatic castration-resistant prostate cancer (mCRPC), patients present visceral metastases with or without neuroendocrine differentiation in 20% of cases. Patients and methods We assessed the efficacy and toxicity of a platinum-based chemotherapy regimen in mCRPC patients with either neuroendocrine differentiation defined by high serum levels of chromogranin A (CgA) and neuron-specific enolase (NSE) or visceral metastases. Patients received the combination of carboplatin and etoposide every 3 weeks. Efficacy end points included prostate-specific antigen (PSA) and neuroendocrine marker response, objective response and toxicity. Results Of the 60 patients included from April 2005 to January 2008, 78.6% had bone metastases, 46.4% had lymph node involvement and 57.1% had liver and/or lung localizations. The objective response rate was 8.9% in the 46 patients with measurable disease. A neuroendocrine response was observed in 31% of cases for NSE and 7% for CgA. The PSA response rate was 8%. The most common grade 3–4 treatment-related toxic effects were neutropenia (65.5%), thrombocytopenia (32.7%) and anemia (27.3%). There was 7.2% febrile neutropenia, with one toxicity-related death. The median follow-up was 9.3 months [95% confidence interval (CI) 0.2–27.1] and the median overall survival 9.6 months (95% CI 8.7–12.7). Conclusion The benefit–risk ratio of this regimen seems unfavorable due to poor response and high toxicity.

Summary Background Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. Methods TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov, number NCT00619268. Findings Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29·5% (26 of 88 patients, 95% CI 20·0–39·1) in group A, 35·7% (15 of 42, 21·2–50·2) in group B, and 61·0% (25 of 41, 46·0–75·9) in group C. Median PFS was 8·2 months (95% CI 7·0–9·6) in group A, 8·2 months (5·5–11·7) in group B, and 16·8 months (6·0–26·0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. Interpretation The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. Funding French Ministry of Health and Wyeth Pharmaceuticals.

Background:Imatinib evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT). Patients and methods:Forty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon’s optimal two-stage phase II study (P 0 =10%,P 1 =30%,a=5%, b=10%). The primary end point was non-progressive at 3 months (RECIST). Results:The study population consisted of 28 women and 12 men, with a mean age of 41 (range 20‐72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease. Conclusion:Imatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.

Objective: To assess the efficacy of capecitabine plus docetaxel (XT) versus epirubicin plus docetaxel (ET) as first-line therapy for metastatic breast cancer (MBC). Patients and Methods: Patients with no prior chemotherapy for MBC were randomized to 3-weekly cycles of either XT (capecitabine 1,000 mg/m2 twice daily, days 1–14; docetaxel 75 mg/m2, day 1) or ET (epirubicin 75 mg/m2, day 1; docetaxel 75 mg/m2, day 1). The primary endpoint was non-progression rate 6 months after randomization. The planned sample size was 106 patients based on a randomized, phase II selection design. Results: Between April 2004 and January 2007, 68 patients were randomized, giving 82% power to select the best regimen according to a 6-month non-progression rate. Slow accrual led to premature study termination. Baseline characteristics were generally well balanced between arms. The 6-month non-progression rates were 75.8% with XT versus 65.7% with ET (p = 0.36). After 42 months’ median follow-up, median progression-free survival was 12.4 versus 6.8 months, respectively (p = 0.040). The safety profiles were consistent with previous experience. Conclusion: Further larger studies are warranted to validate these results. Despite more grade 3 hand-foot syndrome, first-line XT may be a valid alternative to ET, potentially improving efficacy.

e21031Background: Therapeutic response in ALK+ NSCLC is driven by heterogeneous mechanisms of resistance. Liquid biopsy (LB) offers a non-invasive approach to study the tumor genomic landscape unde...

Background: This prospective multicentric phase II study aimed to confirm the results of the C5R protocol of high-dose methotrexate (MTX)-based chemotherapy (CT) for immunocompetent primary central nervous system lymphoma. Patients and methods: A total of 99 patients received age-adapted CT (C5R protocol) followed by radiotherapy. Patients younger than 61 years (group 1, n = 45) received the full C5R with MTX, doxorubicin, vincristine, cyclophosphamide, and cytarabine. Patients aged 61-70 years (group 2, n = 36) received reduced doses. Patients older than 70 years (group 3, n = 18) received four courses of MTX, cyclophosphamide, and etoposide. Results: Median age was 63 years and 51% of patients had performance status of more than one. Seventeen patients died of toxicity during CT. Complete response was achieved in 56%, 53%, and 28% of patients in groups 1, 2, and 3, respectively. With a median follow-up of 83 months, the 5-year progression-free survival was 31%, 28%, and 11% and the 5-year overall survival 42%, 31%, and 17% for groups 1, 2, and 3, respectively. Leukoencephalopathy occurred in 32% of assessable patients, in both group 1 and groups 2-3. Conclusion: The C5R protocol was feasible in the multicentric setting with favorable long-term survival in patients younger than 60 years. Despite dose adaptation, results in older patients were disappointing.

Summary Background & aims Adjuvant chemotherapy has frequently been associated with weight gain after breast cancer diagnosis. We aimed to prospectively evaluate body weight variations in French patients with early breast cancer. Methods This prospective observational study included 272 breast cancer patients who were candidates for adjuvant chemotherapy. Weight and body mass index were measured at baseline visit, then at 9 and 15 months from baseline (6 and 12-month post-chemotherapy). At baseline visit, information on the benefits of weight gain prevention and healthy diet was given by a dietician. Univariate logistic regression was performed to test the association between weight gain and potential predictive factors. Results Thirty percent of patients gained weight during the year before diagnosis, 26% were overweight and 15% were obese. At one year, the mean weight change was +1.5 kg (SD = 4.1) and +2.3% (SD = 6.0); 60% of the cohort had gained weight, with a median increase of 3.9 kg (SD = 3.0) and 5.9% (SD = 4.4). Reported weight gain during the year before diagnosis appears to be the only factor associated with the absence of post-chemotherapy weight gain (OR = 0.54, 95% CI [0.31–0.95], p = 0.034). Conclusion Body weight increased in the post-chemotherapy period in French breast cancer survivors, even when given dietary recommendations. Appropriate weight management interventions with nutritional follow-up and physical activity programs are needed.

Les instances de l’Universite Claude Bernard Lyon 1 (UCBL) ont pris l’initiative de mettre en place un observatoire de la sante, l’OSPEL (Observatoire de la Sante des Personnels de l’Universite Lyon 1) dont la mission est de rapporter des resultats epidemiologiques sur la sante des personnels universitaires. Une premiere etude avait pour objectifs de : 1/ recueillir les thematiques de sante que le personnel desirait voir aborder par l’OSPEL et 2/ de tester la methodologie d’enquete par questionnaire auto-administre via internet aupres d’un echantillon representatif de l’UCBL. En decembre 2008, un echantillon de 15 % de la population professionnelle universitaire (n = 694) a ete invite par courrier electronique (e-mail) a repondre a un questionnaire auto-administre, disponible sur internet. Un echantillon de 607 personnes a recu cet e-mail et 242 agents ont repondu (39,9 % de participation). Un facteur de ponderation a ete applique aux reponses pour redresser la base de l’echantillon des repondants et la rendre representative de la population des professionnels de l’UCBL. Les repondants ont choisi prioritairement trois thematiques, « Qualite de vie-Sante Globale-Bien-etre », « Sante mentale-Stress » et « Risques professionnels » comme thematiques a aborder prioritairement par l’OSPEL. Les repondants etaient en majorite des femmes (63,5 %), des personnels administratifs et techniques (56,8 %) ainsi que des titulaires (77,3 %). L’interet de cette etude a porte sur la reactivite et l’ubiquite de la methodologie internet/intranet qui a permis de cibler aisement les attentes en matiere de sante des personnels universitaires. Cette enquete constitue une premiere etape a la mise en place d’investigations epidemiologiques ciblees en adequation avec les attentes du personnel UCBL. Les prochaines enquetes devront tenir compte des contraintes materielles et temporelles suggerees dans cette etude.

Trabectedin was recently approved for patients failing doxorubicin, the standard treatment for advanced/metastatic sarcoma. This retrospective study aimed to compare trabectedin efficacy between compassionate use in unselected patients and clinical trials. From May 1999 to January 2006, 92 patients were treated at the Centre Léon Bérard, either in phase II studies or on a named patient compassionate basis. All cases were retrospectively analyzed to assess trabectedin efficacy in terms of response, progression-free, and overall survival.The objective response rate was 10% (N=9): 4% (N=2) for patients treated in compassionate use program and 16% (N=7) for those in clinical trials (P=0.18); 26 (28%) patients had stable disease for at least 6 months, 11 (23%) in the compassionate group and 15 (33%) in clinical trials. Median progression-free and overall survivals were, respectively, 2.2 [95% confidence interval (CI): 1.9-3.6] and 8.9 (95% CI: 6.4-14.2) months for all patients, 2.3 (95% CI: 1.9-4.3) and 10.4 (95% CI: 6.9-24.2) months for patients in clinical trials and 1.8 (95% CI: 1.4-3.4) and 6.4 (95% CI: 3.3-14.2) months for patients under compassionate treatment. In this retrospective analysis, the reported grade 3-4 toxicities were increased transaminase (34 patients, 37%) and neutropenia (38 patients; 42%). Higher efficacy was observed in phase II studies than with compassionate treatment, but no significant difference remained after adjustment in multivariate analysis for performance status, a well-established prognosis factor. The safety and tolerability of trabectedin shown in clinical trials is confirmed for patients in real-life situation treated in compassionate use programs, but its benefit is higher for patients with performance status 0-1.

Purpose/Objective(s) Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, partly because of radiotherapy resistance leading to loco-regional recurrences (LRR). The ProfiLER (Profilage LYric et Region, NCT01774409) clinical trial aims at establishing a simple genetic profile of metastatic cancers in order to offer patients personalized molecular targeted therapies. In the breast cancer area, the genomic profiling of a population who ultimately became metastatic, and its correlation with the patient outcome years after LRR, provided an opportunity to identify post hoc biomarkers of the initial radiation resistance. The aim of the present study was to determine if specific tumor genetic alterations were associated with radiation resistance, defined as a LRR despite optimal surgery, radiotherapy, and systemic adjuvant therapies, in a ProfiLER series. Materials/Methods Genetic profile of 162 BC patients’ tumors included in ProfiLER between 2013 and 2016 were analyzed using Next-Generation-Sequencing and Comparative-Genomic-Hybridization tests. Patients and tumor characteristics were analyzed for association with genomic rearrangements (mutations, amplification, homozygous deletions). Only gene alterations observed in >3% of the tumors, or included in well-known molecular pathways (PI3 Kinases pathway, MAP Kinases pathway, Tyrosine Kinase receptors family) were selected. The Cox multivariate analysis was based on (P3% of tumors. PIK3CA and ROS1 mutations were statistically correlated to the risk of LRR. A median loco-regional progression free survival (LRPFS) of 19.8 years was reported for PIK3CA mutation carriers (n = 34, 21%) versus 9.1 years for wild-type patients (HR = 0.29, 95% CI = 0.13-0.64, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor of LRR using multivariate analysis (HR = 0.27, 95% CI = 0.09-0.82), P = 0.02). ROS1 mutated cancer patients (n = 8, 4.9%) had a median LRPFS of 4 years versus 16.1 years for wild-type patients (HR = 2.5, 95% CI = 1.74-7.05, P = 0.08 in univariate analysis), but was not identified as an independent LRR risk factor (HR = 2.45 95% CI = 0.83-7.26, P = 0.11 in multivariate analysis). Other mutations and amplifications were not associated with LRR. Among relapsing patients, the median time to LRR was nearly significantly different regarding status of the PIK3CA mutations, with 8.6 years for mutated patients versus4.7 years for non-mutated patients (P = 0.09). Conclusion PIK3CA mutation was associated with a lower risk of LRR in this BC population. ROS1 mutation was marginally associated with a higher risk of LRR, possibly because of a limited population. Results suggest PIK3CA and ROS1to be possible biomarkers of radio-sensitivity.

Resume Objectifs La douleur cancereuse reste mal prise en charge en France. Une enquete qualitative de type sociologique permet d’apporter des elements actualises sur la question de la douleur au travers des recits des personnes malades et des soignants. Une attention sur l’utilisation de la reglette echelle visuelle analogique (EVA) permet d’etudier la communication soignant–patient dans le processus d’evaluation de la douleur. Methode Des focus groups de patients, d’une part, et de soignants, d’autre part, (groupes soignants et groupes medecins) ont ete organises a partir de deux etablissements specialises en cancerologie de la region Rhone-Alpes. Une methode d’animation centree sur la dynamique de groupe a favorise les interactions a l’interieur des groupes. Une analyse sociologique comparative et thematique a permis de degager les conclusions. Resultats Les differences de representations de la douleur entre patients et soignants amenent a une problematique qui reste conflictuelle. La subjectivite de la douleur est vecue par les patients alors que les professionnels cherchent a en degager une vision objectivee. La reglette EVA reintroduit la subjectivite du patient dans l’evaluation de la douleur. Le conflit entre une mesure EVA subjective et l’analyse objective du soignant met celui-ci en difficulte. La mesure ne peut alors etre validee par le soignant. Conclusions La possibilite d’un nouveau contrat ou le patient est reconnu partenaire dans la gestion de la douleur n’est possible qu’avec une evolution de la culture professionnelle soignante mais necessite egalement le developpement des competences du patient.

Radiation therapy remains the only treatment that provides clinical benefit to children with diffuse brainstem tumors. Their median survival, however, rarely exceeds 9 months. The authors report a prospective trial of front-line chemotherapy aimed at delaying radiation until time of clinical progression. The aim was to investigate the possibility that radiotherapy would maintain its activity in children whose disease progressed after chemotherapy. Twenty-three patients took part in this protocol, the BSG 98 protocol, which consisted of frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules. Each cycle included three courses delivered monthly; the first course was 1,3-bis(2-chloroethyl)-1-nitrosourea– cisplatin, and the second and third were high-dose methotrexate. Three patients underwent one cycle; 5 patients each, two and three cycles; and 10 patients, four cycles. Twenty of the 23 patients eventually received local radiation therapy. A historical cohort of 14 patients who received at least local radiation therapy served as controls. Four patients experienced severe iatrogenic infections, and 11 patients required platelet transfusions. Median survival increased significantly in patients participating in the protocol compared to that in the historical controls (17 months, 95% confidence interval [CI], 10–23 months, vs. 9 months, 95% CI, 8–10 months; p = 0.022), though hospitalization was prolonged (57 vs. 25 days, p = 0.001). Although frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules significantly increases overall median survival, its cost from infection and hospitalization deserves honest discussion with the children and their parents.

The optimal therapy of oligodendrogliomas remains uncertain. Although chemosensitive, these tumors are not chemocurable. We investigated whether chemotherapy delays the need for radiation therapy (RT) without decreasing length and quality of survival.Among 89 patients treated for oligodendrogliomas at the Centre Léon Bérard of Lyon from 1982 to 1999, 59 patients fitted inclusion criteria, having had centrally reviewed pure oligodendroglioma requiring treatment. According to the WHO's classification 35 patients had Grade III and 24, Grade II oligodendrogliomas.According to the intent to treat, patients were retrospectively classified in three groups as exclusive RT (Group 1), radio-chemotherapy (Group 2), or exclusive chemotherapy (Group 3). Median progression-free survival (PFS): was 47 months [95% confidence interval (CI) 39-56], and median overall survival (OS) was 109 months (95% CI 83-134). In univariate analysis, PFS was correlated with frontal location and WHO classification; OS was correlated with frontal location and Post-operative Karnosky performans status both appearing as independent prognostic factors for OS in multivariate analysis. There was no significant difference between the treatment groups with regard to PFS (P = 0.82) and OS (P = 0.64). In the group of patients treated with exclusive chemotherapy the 5-year PFS and OS rates were 44 and 71%, respectively.Front-line exclusive chemotherapy results in prolonged OS in patients with confirmed pure oligodendroglioma. Whether this strategy improves quality of life remains debatable.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: In patients with advanced NSCLC: to establish clinical effectiveness, in terms of overall survival (OS) and progression free survival and (PFS), of maintenance therapy compared with placebo or observation, which is considered as standard of care; to compare clinical effectiveness, in terms of OS and PFS, of different agents or combinations in the maintenance setting (i.e. chemotherapy vs targeted agent, chemotherapy plus targeted agent vs chemotherapy or targeted agent), and to assess the toxicity of maintenance therapy.

Background Surgery is the only curative treatment in patients with colorectal liver metastases (CLM), but only 10–20% of patients are eligible. High Intensity Focused Ultrasound (HIFU) technology is of proven value in several indications, notably prostate cancer. Its intra-operative use in patients with CLM has not previously been studied. Preclinical work suggested the safety and feasibility of a new HIFU device capable of ablating volumes of up to 2cm x 2cm in a few seconds. Methods We conducted a prospective, single-centre phase I-IIa trial. HIFU was delivered immediately before scheduled hepatectomy. To demonstrate the safety and efficacy of rapidly ablating liver parenchyma, ablations were performed on healthy tissue within the areas scheduled for resection. Results In total, 30 ablations were carried out in 15 patients. These ablations were all generated within 40 seconds and on average measured 27.5mm x 21.0mm. The phase I study (n = 6) showed that use of the HIFU device was feasible and safe and did not damage neighbouring tissue. The phase IIa study (n = 9) showed both that the area of ablation could be precisely targeted on a previously implanted metallic mark (used to represent a major anatomical structure) and that ablations could be undertaken deliberately to avoid such a mark. Ablations were achieved with a precision of 1–2 mm. Conclusion HIFU was feasible, safe and effective in ablating areas of liver scheduled for resection. The next stage is a phase IIb study which will attempt ablation of small metastases with a 5 mm margin, again prior to planned resection. Trial Registration ClinicalTrials.govNCT01489787

Resume Objectif de l'etude Etudier le recalage deformable des donnees anatomiques scanographiques dans le cadre d'une radiotherapie conformationnelle avec blocage respiratoire par deux etudes paralleles. Patients et methodes Une serie de 22 patients atteints d'insuffisance respiratoire severe, traites entre avril 2002 et novembre 2005 par irradiation conformationnelle avec blocage respiratoire, a donc ete analysee. La premiere etude a analyse la reproductibilite du blocage respiratoire actif pour chaque patient tout au long du traitement : un deplacement tumoral moyen de 10 mm a ete detecte. La seconde etude avait pour but de simuler une imagerie quadridimensionnelle a partir de donnees tridimensionnelles en blocage respiratoire en utilisant une methodologie d'interpolation des champs de deformation tridimensionnelle, la precision obtenue etant de l'ordre de 3 mm. Resultats En ce qui concerne l'etude clinique, la duree mediane de suivi etait de 22 mois, le taux de controle local etait de 28 %. La rechute metastatique restait l'evenement le plus frequent. Concernant, dans l'etude de modelisation, le blocage respiratoire a ete efficace chez six des huit patients avec des mouvements inferieurs a 6 mm. La simulation quadridimensionnelle a partir d'image tridimensionnelle s'est averee fiable et a pu permettre de simuler une respiration pour un plan de traitement quadridimensionnel. Conclusion La technique de traitement est realisable malgre l'insuffisance respiratoire severe. La methode d'acquisition artificielle quadridimensionnelle permet d'esperer une simulation correcte en cas de rythme respiratoire irregulier et pourrait etre utilisee pour une dosimetrie quadridimensionnelle.

L’etude a pour but de tester la faisabilite d’une prise en charge precoce a domicile des aplasies febriles sans facteurs de mauvais pronostic. Sur 517 episodes de neutropenies febriles enregistres entre 07/99 et 06/01, seuls 52 cas ont beneficie de cette prise en charge avec Cefepime 2g 2 fois par jour. Dans les autres cas, il existait des facteurs de mauvais pronostic ou des echecs organisationnels. Sur les 52 cas, 50 cas ont ete des succes avec retour a domicile rapide, antibiotherapie efficace et absence de rehospitalisation. Dans les 2 autres cas, le depart a du etre differe pour complications. Cette strategie est donc tout a fait optimale sur une population correctement selectionnee. Les nouveaux scores pronostics de la neutropenie febrile et le developpement croissant des soins a domicile devraient permettre d’elargir la population cible pour cette prise en charge ambulatoire.

Interleukin-2 (IL2) or/and interferon (IFN) are routinely used for treating patients with metastatic renal cell cancer. However, results are disappointing since most patients experience treatment failure. Within 6 years, the Groupe Francais d’Immunotherapie enrolled 782 patients in successive multicenter trials using cytokine regimens. Univariate and multivariate analyses were performed on this large prospective database to identify prognostic factors for treatment response or failure. We identified two independent factors predictive of response to cytokine treatment: having only one metastatic organ site and receiving a combination of cytokine treatments. We also identified four independent factors predictive of rapid progression under treatment: presence of hepatic metastases, short interval from renal tumor to metastases (

Objectifs ART-ORL est un essai multicentrique qui a evalue d’une part les couts de la mise en œuvre de la radiotherapie conformationnelle avec modulation d’intensite (RCMI) par differentes techniques d’arctherapie volumetrique modulee en France et d’autre part l’efficacite et la toxicite de ce traitement. Les implications de l’utilisation du cetuximab chez des patients recevant une arctherapie volumetrique modulee ne sont pas encore bien decrites. Cette etude est une analyse exploratoire a partir des donnees prospectives et multicentriques de cet essai soutenu par l’Institut national du cancer (Inca). Patients et methodes Les criteres d’inclusion etaient les patients atteints d’un carcinome epidermoide ou indifferencie du cavum, de l’oropharynx ou de la cavite buccale, de stade I a IV, sans metastase, non opere, avec une irradiation des aires ganglionnaires cervicales bilaterale. Resultats Cent quatre-vingt patients ont ete inclus. L’âge median etait de 56 ans. Cent dix-huit patients etaient pris en charge pour un carcinome epidermoide de l’oropharynx (67,8 %), 38 pour un carcinome indifferencie du cavum (21,8 %), 17 pour un carcinome epidermoide de la cavite buccale (9,8 %) et un pour une double localisation oro- et nasopharyngee. Vingt neuf patients ont recu du cetuximab. Ces patients etaient plus âges (p Conclusion Aucune difference significative de survie ou de toxicite n’a ete mise en evidence entre les patients traites par une technique d’arctherapie volumetrique modulee, avec ou sans cetuximab. Ces resultats doivent etre interpretes en tenant compte du faible nombre de patients traites par cetuximab dans l’essai ART-ORL.

LBA100 Background: ProfiLER (NCT01774409) is a molecular profiling clinical trial exploring cancer cell genomic alterations in pts with advanced disease to guide treatment. Methods: Pts with confirmed diagnosis of advanced cancers are eligible. DNA extracted from either archival or fresh collected tumor samples was analyzed by targeted exon sequencing of 60 cancer related genes and whole genome array comparative genomic hybridization (CGH). A multidisciplinary molecular board analyzes genomic data and recommends molecular targeted therapies (MTT) when actionable alterations are found. Results: As of Jan 2017, 2490 pts (55% female, median age 59, range 1-90) were consented; 1826 (73.3%) tumors were analyzed, 301 (12%) are ongoing (not done in 363 pts (14.6%) for technical issues). Tumor types were colorectal (10.3%), gyneco (9.5%), breast (8.8%), head & neck (7.1%) carcinomas, sarcomas (7.1%) and brain tumors (6.5%). 940/1826 pts (51.5%) had at least 1 actionable mutation (AM): 579 pts with only one AM, while 358 with 2 or more AM (up to 6). Mutations (including substitutions and small indels), amplifications and homozygous deletions (HD) were observed respectively in 55.3%, 42.1% and 25.5% of tumor samples. The most common AM were on KRAS (n = 156; 8.5%), PIK3CA (n = 150; 8.2%), CDKN2A HD (n = 174; 9.5% ), PTEN HD (n = 49, 2.7%), CCND1 (n = 97; 5.3%), FGFR1 (n = 56; 3.1%), MDM2 (n = 53; 2.9%), HER2 (n = 42; 2.3%) and HER1(n = 41; 2.2%). MTT were recommended in 644 pts. Among them, 101 (gyn [28%], GI [18%], breast [12%]) initiated a recommended MTT. Collection of treatment data is ongoing for 202 pts. MTT received were mTOR inhibitors (39%), anti-angiogenic TKI (21%), EGFR TKI (9.8%), inhibitors of cell cycle (6.9%). Best responses were CR (n = 2, 2.3%), PR (n = 13, 15.1%), SD (n = 29, 33.7%), PD (n = 42, 48.8%), with a median PFS of 2.8 months (95% IC: 2.2-3.5). 24% are alive progression free at 6 months. Updated data will be presented at the meeting. Conclusions: In this series of 2490 cancer pts, CGH and NGS identified actionable alterations on 51% of pts, with treatment recommendation in 35%. Most patients treated derived benefit from the recommended MTT, but these represent a minority of the whole population screened. Clinical trial information: NCT01774409.

1078 Background: Real-life data may help checking that public investments match closely medical needs. During the last decade, several drugs have been released on the market for MBC on the basis of a potential impact on overall survival (OS). Based on the large real-life ESME cohort, we aimed to describe the time evolution of MBC OS according to main phenotypes. Methods: ESME is a unique MBC national cohort including all consecutive patients (pts) who initiated treatment for MBC between 1/01/08 and 31/12/14 in the 18 French comprehensive cancer centres. ESME collects retrospective data using clinical trial-like methodology including quality assessments. Database lock was 8/12/2016. Primary objective was the impact of year of MBC diagnosis on OS. Multivariate Cox regressions were used with adjustment for main prognostic covariates. Results: 15170 out of 16703 pts in ESME had full IHC data allowing their classification as HR+HER2- (N=9922), HER2+ (N=2863), or HR-HER2- (N=2321) cases. Median FU and OS for the whole cohort are 4.05 yrs [95 CI: 3.98-4.12], and 3.1 yrs [95 CI: 3.03-3.18] respectively. In the adjusted multivariate analysis, year of MBC diagnosis, age at MBC, subtype (using HER2+ as reference), disease-free interval (DFI), visceral involvement, and number (nbr) of metastatic sites are significant OS predictors (table) although with low effect for the first item. Age at MBC, DFI, visceral involvement, and nbr of metastatic sites remained significant prognostic variables in subtypes. Year of diagnosis was no longer significant in HR+HER2- nor HR-HER2- cases (HR=0.997, p=0.71 and HR=0.997, p=0.84), while it was highly significant in HER2+ cases (HR=0.91, p

11054 Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y90 (Arm A) or 1110MBq Y90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y90OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2nd injection of 90Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90Y-OTSA101 with a recommended dose of 1110MBq of 90Y. Clinical trial information: NCT01469975.

Introduction Les patients âges sont les premiers concernes par les CBNPC et leur prise en charge rarement evaluee specifiquement. L’objectif de cette etude est de decrire en vraie vie en France les strategies therapeutiques de 1 re ligne incluant Bevacizumab chez des patients âges atteints de CBNPC. L’etude vise egalement a decrire leurs caracteristiques, survie sans progression, survie globale et qualite de vie ainsi que la tolerance au traitement. Methodes AVANTAGE est une cohorte prospective multicentrique, conduite chez des patients ≥ 65 ans, debutant une 1 re ligne de chimiotherapie associee a bevacizumab pour le traitement du CBNPC. Les donnees ont ete recueillies a l’inclusion (07/2013 a 12/2015), puis tous les 3 mois pendant 18 mois. Les raisons de non-prise en charge par bevacizumab ont ete recueillies pendant 6 mois. Resultats Deux cent soixante-dix-sept patients traites ont ete inclus dans 72 centres (50 % de CHG, 24 % de cliniques, 21 % de CHU et 5 % de CLCC). Un total de 248 patients ont ete retenus pour l’analyse : hommes (75 %), 65–69 ans (43 %) et ≥ 70 ans (57 %), index ECOG a 0 (42 %), score du questionnaire G8 > 14 (36 %), anciens fumeurs (64 %), stade IV (96 %), index de comorbidite de Charlson ajuste sur l’âge ≤ 3 (43 %). L’association sels de platine-pemetrexed-bevacizumab a ete prescrite chez 186 (75 %) patients (avec cisplatine dans 55 % des cas et carboplatine dans 45 % des cas). Les 62 (25 %) patients n’ayant pas beneficie de cette association ont recu d’autres agents (dont l’association carboplatine-paclitaxel-bevacizumab dans 69 % des cas). La posologie initiale de bevacizumab, instaure des le 1 er ou 2 e cycle de chimiotherapie chez 95 % des patients, etait de 7,5 (70 %) ou 15 (23 %) mg/kg/3 semaines. L’association sel de platine-pemetrexed-bevacizumab a ete prescrite chez 80 % des patients (85/106) de 65–69 ans et chez 71 % des patients (101/142) ≥ 70 ans. Cette association a ete plus frequente chez les patients de 65–69 ans (46 % vs 34 %), avec ECOG a 0 (45 % vs 33 %), score du questionnaire G8 > 14 (38 % vs 29 %), ou index de comorbidite de Charlson ajuste ≤ 3 (45 % vs 36 %). Les principales raisons de non-prescription de bevacizumab (chez les 108 patients repertories) etaient : âge du patient (18 %), localisation centrale de la tumeur (18 %), implication des gros vaisseaux (18 %), maladie arterielle (14 %) et ECOG ≥ 2 (10 %). Conclusion AVANTAGE montre que chez des patients âges eligibles a une chimiotherapie de 1 re ligne avec du bevacizumab, l’association la plus frequemment utilisee est celle d’un sel de platine et du pemetrexed (75 % des cas).

Background In breast cancer patients, a lack of physical activity (PA) is 1 causative factor of weight gain during adjuvant treatment. It may increase the risk of treatment adverse effects, comorbidities, and deleterious long-term outcomes. Objective We aimed to describe the evolution of PA level and sedentary behavior in breast cancer patients between diagnosis and adjuvant chemotherapy onset following surgery and identify predictive factors associated with these changes early after breast cancer diagnosis. Methods Baseline data of 60 patients enrolled in a pilot randomized controlled trial of PA are presented. PA levels were estimated at adjuvant chemotherapy onset after surgery and retrospectively for the period at diagnosis. Height, weight, waist circumference, and bioelectrical impedance were measured at chemotherapy onset. Linear regression analysis evaluated factors associated with relative changes of PA level and sedentary behavior. Results Moderate PA decreased and sedentary behavior increased between diagnosis and chemotherapy onset. A grade III breast cancer was associated with a greater decrease in PA level. Conversely, keeping a professional occupation and adherence to nutritional guidelines were associated with maintained PA level. The majority (88%) of patients had excessive adiposity at chemotherapy onset. Conclusions There was a significant deterioration of PA level between diagnosis and chemotherapy onset, and deleterious adiposity was present in most patients. Implications for practice This study further emphasizes the need to motivate breast cancer patients toward engaging in a healthy lifestyle early after diagnosis and adhering to PA programs, which should be included in their clinical management.

We read with great interest Richard ten Broek and colleagues’ meta-analysis about the use of four diff erent anti-adhesion barriers. Reoperation for adhesive small bowel obstruction was the primary outcome. The authors suggest their results should inform the development of guidelines for the use of barriers to prevent long-term adhesion-related complications for abdominal surgery in general. However, these results are not applicable to surgical oncology. In stage IV colorectal cancer, which is the most frequent cancer aff ecting the abdomen, advances in chemotherapy during the past decade have enabled us to increase the number of patients treated with repeated abdominal surgery and therefore, exposed to adhesiolysis-related morbidity. As ten Broek and colleagues noted, adhesiolysis is associated with an increase in bowel injury and septic complications. Moreover, adhesiolysis time predicts enterotomy. Reoperation for adhesive small bowel obstruction is a rare event and needs a long follow-up period if chosen as a primary endpoint in studies. Hence, adhesive small bowel obstruction is probably not the most clinically relevant outcome nor the most suited to clinical trials when assessing the consequences of adhesions in surgical oncology. Instead, a more realistic primary outcome should be chosen. Such an outcome should allow objective evaluation and should be assessable over a short timeframe. In surgical oncology, serious adverse events and adhesiolysis time might be of value.

Hemkens and colleagues investigated the effects of treatment on mortality in routinely collected data and subsequent randomised trials.1 They found that observational studies with routinely collected data substantially overestimated the effects of treatment, despite the use of propensity scores to address confounding bias. This overestimation might, however, be partially due to the selection of studies. In randomised controlled trials, a pitfall is choosing a control that reflects the realities of medical care, and a major …