Dominique Genet

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I<O and r24) were used to estimate CircAct. Of 130 patients with baseline CircAct assessments, 96 had baseline HRQoL data. I<O was confirmed to correlate with global quality of life, physical functioning, social functioning, fatigue, and appetite loss (r > |0.25|; P < 0.01). I<O further independently predicted for overall survival with a hazard ratio of 0.94 (P < 0.0001). The associations between CircAct parameters, HRQoL, and survival, which were shown in this international study involving previously untreated metastatic colorectal cancer patients, confirm prior single-institution findings in mostly pretreated metastatic colorectal cancer patients. The circadian timing system constitutes a novel therapeutic target. Interventions that normalize circadian timing system dysfunction may affect quality of life and survival in cancer patients.

In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer.For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation.Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively.Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.

Purpose The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders. Methods This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial. Results In the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10 –7 ), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p&lt;0·001). Patients with a SPECTRA Score &gt;0·02 had a lower OS in the training cohort (p&lt;0·0001), in the validation cohort (p&lt;0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41). Conclusion A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies. Trial registration Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029 . Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717 .

Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%).In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.NCT00303771.

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

During the COVID-19 pandemic, teleconsultation was implemented in clinical practice to limit patient exposure to COVID-19 while monitoring their treatment and follow-up. We sought to examine the satisfaction of patients with breast cancer (BC) who underwent teleconsultations during this period.Eighteen centres in France and Italy invited patients with BC who had at least one teleconsultation during the first wave of the COVID-19 pandemic to participate in a web-based survey that evaluated their satisfaction (EORTC OUT-PATSAT 35 and Telemedicine Satisfaction Questionnaire [TSQ] scores) with teleconsultation.Among the 1299 participants eligible for this analysis, 53% of participants were undergoing standard post-treatment follow-up while 22 and 17% were currently receiving active anticancer therapy for metastatic and localised cancers, respectively. The mean satisfaction scores were 77.4 and 73.3 for the EORTC OUT-PATSAT 35 and TSQ scores, respectively. In all, 52.6% of participants had low/no anxiety. Multivariable analysis showed that the EORTC OUT-PATSAT 35 score correlated to age, anxiety score and teleconsultation modality. The TSQ score correlated to disease status and anxiety score.Patients with BC were satisfied with oncology teleconsultations during the COVID-19 pandemic. Teleconsultation may be an acceptable alternative follow-up modality in specific circumstances.

Purpose A recent study identified a prognostic model for survival in metastatic colorectal cancer patients which included WBC count, alkaline phosphatase (AP), number of metastatic sites, and patients’ self-reported social functioning. The aim of this research is to validate this model on data from an independent sample. Patients and Methods This validation study is based on a prospective randomized controlled trial in patients with metastatic colorectal cancer conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Chronotherapy Group. Overall, 564 patients in 10 countries were enrolled. For the purpose of this independent validation, patients with health-related quality of life (HRQOL) baseline data were analyzed. HRQOL was assessed using the EORTC Quality of Life Questionnaire C30 (QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. Results The previous model with an additional adjustment, by stratification for sex, was replicated and its parameters were confirmed to independently predict survival: WBC count with an hazard ratio (HR) of 1.31 (95% CI, 1.021 to 1.698; P = .034); AP with an HR of 1.53 (95% CI, 1.188 to 1.979; P = .001); number of sites involved with an HR of 1.90 (95% CI, 1.531 to 2.364; P &lt; .0001); and patients’ self-reported social functioning with an HR of 0.94 (95% CI, 0.905 to 0.976; P = .001). The latter translates into a 6% increase in the likelihood of an earlier death for every 10-point decrease in the social functioning scale of the EORTC QLQ-C30. Conclusion This study provides confirmatory evidence of the independent prognostic value of patients’ self-reported social functioning in patients with advanced colorectal cancer.

Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population.Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator's choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria.About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75-91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT).Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.

Several predictors of metastatic colorectal cancer (mCRC) outcomes have been described. Specific geriatric characteristics could be of interest to determine prognosis.Elderly patients (75+) with previously untreated mCRC were randomly assigned to receive infusional 5-fluorouracil-based chemotherapy, either alone (FU) or in combination with irinotecan (IRI). Geriatric evaluations were included as an optional procedure. The predictive value of geriatric parameters was determined for the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).From June 2003 to May 2010, the FFCD 2001-02 randomised trial enrolled 282 patients. A baseline geriatric evaluation was done in 123 patients; 62 allocated to the FU arm and 61 to the IRI arm. The baseline Charlson index was ≤1 in 75%, Mini-Mental State Examination was ≤27/30 in 31%, Geriatric Depression Scale was >2 in 10% and Instrumental Activities of Daily Living (IADL) was impaired in 34% of the patients. Multivariate analyses revealed that no geriatric parameter was predictive for ORR or PFS. Normal IADL was independently associated with better OS. The benefit of doublet chemotherapy on PFS differed in subgroups of patients ≤80 years, with unresected primary tumour, leucocytes >11,000 mm3 and carcinoembryonic antigen >2N. There was a trend towards better OS in patients with normal IADL.The autonomy score was an independent predictor for OS. A trend toward a better efficacy of doublet chemotherapy in some subgroups of patients was reported and should be further explored.

BackgroundPrevious studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.Patients and methodsA pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5–24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy.ResultsThe rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991–1999 period) to 41.5% (2000–2006 period) and 44.8% (2007–2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80–0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01–1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87–1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients.ConclusionOverweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.

Importance The optimal maintenance strategy after induction chemotherapy with anti–epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. Objective To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. Design, Setting, and Participants The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]–UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. Interventions After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. Main Outcomes and Measures The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Results Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). Conclusion and Relevance The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. Trial Registration ClinicalTrials.gov Identifier: NCT02404935

Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC.Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE).Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups.Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.

Background Older patients have frailty characteristics that impair the transposition of treatment results found in younger patients. Predictive factors are needed to help with treatment choices for older patients. The PRODIGE 20 study is a randomized phase II study that evaluated chemotherapy associated with bevacizumab (BEV) or not (CT) in patients aged 75 years or older. Patients and methods Patients underwent a geriatric assessment at randomization and at each evaluation. The predictive value of geriatric and oncologic factors was determined for the primary composite end-point assessing safety and efficacy of treatment (BEV or CT) simultaneously and also progression-free survival (PFS) and overall survival (OS). Results 102 patients were randomized (51 BEV and 51 CT; median age 80 years [range 75–91]). On multivariate analysis, baseline normal independent activity of daily living (IADL) score and no previous cardiovascular disease predicted the primary end-point. High (versus low) baseline Köhne score predicted short PFS and baseline Spitzer quality of life (QoL) score <8, albumin level ≤35 g/L, CA19.9 >2 LN levels above normal and high baseline Köhne score predicted short OS. Survival without deteriorated QoL and autonomy was similar with BEV and CT. On subgroup analyses, the benefit of bevacizumab seemed to be maintained in patients with baseline impaired IADL or nutritional status. Conclusion Normal IADL score was associated with a good efficacy and safety of both BEV and CT. Köhne criteria may be relevant prognostic factors in older patients. Adding bevacizumab to chemotherapy does not impair patient autonomy or QoL.

We report one new case of hemolytic–uremic syndrome (HUS) and one case of digital necrosis after treatment with gemcitabine (Gemzar). Case 1, a 34-year-old man, was given first-line metastatic treatment with gemcitabine for a adenocarcinoma of the pancreas. After a cumulative dose of 10 000 mg/m2 gemcitabine, the onset of subacute renal failure associated with hemolytic anemia of mechanical origin was observed. A diagnosis of probable gemcitabine-induced thrombotic microangiopathy was arrived at. Symptoms resolved after stopping the chemotherapy, in spite of the progression of the disease. Case 2, a 61-year-old man, was administered a combination of gemcitabine and a platinum salt as first-line metastatic treatment for carcinoma of the bladder urothelium. Following a cumulative dose of 10 000 mg/m2 of gemcitabine, the patient suffered from bilateral peripheral vascular disease of somewhat acute onset with hemorrhagic lesions of the finger pads that became necrotic. The work-up was negative and a causal relationship was attributed to gemcitabine. The patient made good progress when given an i.v. infusion of Ilomedine (iloprost trometamol) and chemotherapy was withdrawn. We conclude that gemcitabine must be added to the list of drugs that cause HUS and necrotizing vasculitis.

To assess pelvic (P) and/or paraaortic (PA) lymph node (LN) involvement in patients with primary stage IA-IVA cervical cancer, (18)F-fluorodeoxyglucose (FDG)-PET, and MRI were compared with histological results.Forty patients were prospectively evaluated. Twenty-eight patients underwent radio-chemotherapy (RT-CT) after initial staging and lymph node dissection (LND).PLN metastases were present in 6/31 patients. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) and accuracy in detecting PLN metastases were 67%, 84%, 50%, 91% and 81%, with MRI, and 33%, 92%, 50%, 85% and 81%, with FDG-PET. PALN metastases were present in 5/27 patients. Sensitivity, specificity, PPV, NPV and accuracy were 60%, 73%, 33%, 89% and 70% with MRI and 100%, 77%, 50%, 100% and 81% with FDG-PET in detecting PALN metastasis.FDG-PET is less accurate than MRI for PLN, but more accurate for PALN; FDG-PET cannot replace PA surgical procedures, but could guide them.

15 Background: Compared to observation, maintenance therapy with a fluoropyrimidine +/- bevacizumab showed significant improvement in progression-free survival (PFS) but not in overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC) and disease control after first-line doublet chemotherapy (CT) +/- bevacizumab. Few studies are available on the role of maintenance therapy after induction anti-EGFR-based CT, and the benefit from anti-EGFR maintenance monotherapy during CT-free intervals (CFI) in patients with RAS wild-type (wt) mCRC. Methods: RAS wt unresectable mCRC patients with controlled disease after FOLFIRI + cetuximab (8 cycles) were randomized (1:1) to receive maintenance with bi-weekly cetuximab alone (arm A) or observation (arm B) until disease progression (PD)/unacceptable toxicity/death. Randomization was stratified according to tumor response, center, baseline Köhne Score, CEA and platelet count. In case of tumor progression during the CFI, FOLFIRI + cetuximab was to be reintroduced for 8 cycles, followed by a new CFI. Tumor response was assessed per RECIST1.1 every 8 weeks. The primary objective of this multicenter non-comparative randomized phase II trial was 6-month PFS rate after initiation of maintenance therapy. A total of 134 randomized and evaluable patients (67 per arm) were required (Fleming’s one-step design, one-sided α=5%, β=20%, H0: 40%; H1: 55%). Secondary endpoints were overall response rate (ORR), time to strategy failure, PFS, OS, safety, quality of life, circulating tumor cells and circulating tumor DNA detection and dynamic changes during treatment. Results: From January 2014 to April 2019, 214 patients were included and 139 randomized (67 arm A/72 arm B) in 35 centers. Baseline characteristics were: males, 67%/69%; median age, 64/68 years; ECOG PS 0, 54%/46%; previous adjuvant therapy, 25%/14%; single metastatic site, 58%/47%; right-sided primary, 24%/18%. The ORR in the overall and the randomized population was 55% and 72%, respectively. The median follow-up was 30 months. The 6-month PFS rate after initiation of maintenance therapy was 30% 95%CI[19; 42] in the maintenance arm, and 6% 95%CI[2;14] in the observation arm, with a median PFS of 5.3 95%CI[3.7;6.5] and 2.0 95%CI[1.8;2.8] months, respectively. Any grade treatment-related toxicity, including skin rash (40%/4%), diarrhea (33%/8%), and hypomagnesemia (46%/10%) was more frequent in arm A. Conclusions: Based on the study hypothesis, the cetuximab maintenance arm did not meet the primary objective. However, the clinically meaningful difference in PFS without any overlap in the confidence intervals between the two arms warrants further investigation. Clinical trial information: NCT02404935.

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m(2)/d on D1 and D6 and chronomodulated 5-fluorouracil of 850 mg/m(2) from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m(2)/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3-4 (G3-4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3-4 neutropenia was observed at 21:00 h with a non-significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3-4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3-4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time-finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time-finding design may be used to identify the best time of chemotherapy administration.

The aim of this study was to evaluate with a long follow-up the efficacy of concomitant chemoradiotherapy in non-metastatic inflammatory breast cancer (IBC) and to evaluate the breast conservation rate. Between 1990 and 2000, 66 non-metastatic patients with IBC were treated with chemotherapy and concomitant irradiation. The induction chemotherapy consisted of epirubicine, cyclophosphamide and vindesine, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and 5-fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and six cycles of epirubicine, cyclophosphamide and fluorouracil. Hormonal treatment was given if indicated. Mastectomy was not systemic. Among 65 evaluable patients, 57 (87.6%) achieved a complete clinical response and had a breast conservation. Only six loco regional relapses were noted in six patients with a delay of 20 months and with concomitant metastatic dissemination in four cases. Median disease-free survival (DFS) was 28 months. Median overall survival (OS) was 63 months and median follow-up was 55.5 months. Induction chemotherapy and concomitant irradiation is feasible in patients with IBC, permitting a breast conservation with a high rate of local control with an OS comparable to that of the best recent series.

Adjuvant chemotherapy shows clear benefits in HER2-positive and triple-negative breast cancer (BC). Its benefits are less universal in BCs expressing hormone receptors. The 21-gene Oncotype DX® Breast Recurrence Score test was designed for HR+, HER2– early-stage BC before decision on adjuvant chemotherapy. Its validity and utility was demonstrated prospectively across multiple studies. The observational study PONDx characterized the use of Oncotype DX® Breast in routine practice in France and evaluated its decision impact. Of 882 ER-positive BC patients (67% postmenopausal), most (79%) had N0/Nmic node involvement, grade 2 tumors (68%), tumor size 1–5 cm (88%), and ductal histology (78%). BCs with histopathologically elevated recurrence risk included grade 3: 18%; N1: 21%; Ki67 > 20%: 31%. Recurrence Score results by prognostic category were: <18: 54%, 18–30: 36%; >30: 10%. Compared to recommendations before individual availability of the score, results prompted net absolute reductions in chemotherapy recommendations of 36% (total population), and 29% (grade 3 and/or Ki67 > 20% histologies). Decisions reflected prognostic implications: in the Recurrence Score <18 category, 95% of patients received recommendations of hormonal therapy only, in the >30 category, 97.5% were recommended additional chemotherapy; 95% followed the final recommendations of their physicians. The Recurrence Score provides independent predictive and prognostic information in ER + N0/N1 early BC, including high-risk subgroups. PONDx further characterizes the population where the test is beneficial in real-life use and fits current clinical needs. Oncotype DX® Breast enables relevant net reductions in chemotherapy use, sparing patients from serious toxicities. Its therapeutic implications are highly accepted by physicians and patients.

A liquid chromatography-electrospray mass spectrometry method was developed for the quantitation of vinorelbine (VNB) and two metabolites, vinorelbine N-oxide (VNO) and deacetyl vinorelbine (DAV) in human serum. The limits of quantitation (LOQ) reached 0.5 ng/ml for both VNB and VNO and 1 ng/ml for DAV. The method was proved linear in the range of LOQs up to 1000 ng/ml, and extraction recovery was 80% on average for the three compounds. It was applied to the pharmacokinetic monitoring of vinorelbine and, for the first time, to the detection of VNO in the serum of patients suffering from non-small-cell lung cancer.

This phase II study evaluated docetaxel-5-fluorouracil (5-FU) in locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients were divided into 2 cohorts--those previously treated with chemotherapy and those nonpretreated--that received docetaxel 75 mg/m2 (day 1) plus 5-FU 1,000 mg/m2/day (days 1-5 every 3 weeks). Of 63 patients entered, 20 (31.7%) were pretreated and 43 (68.3%) were nonpretreated. Fifty-nine patients (93.7%) had received prior radiotherapy. After inclusion of 20 patients, the 5-FU dose was reduced to 750 mg/m2/day due to unacceptable toxicity. The overall response rate (ORR) was 20.6% on radiologic review (22.2%, investigator assessment). Pretreated patients achieved an ORR of 25.0% versus 18.6% for nonpretreated patients. This unexpected finding was partly attributed to differences in patient characteristics between the groups. Overall major grade 3 to 4 toxicities comprised neutropenia (66.6%), febrile neutropenia (31.7%), and mucositis (31.7%). Grade 3 to 4 toxicities were lower at the reduced 5-FU dose (750 mg/m2/day): Febrile neutropenia declined from 40.0% to 27.9%; mucositis declined from 55.0% to 20.9%. Three treatment-related deaths occurred (2 with 5-FU 750 mg/m2/day, 1 with 5-FU 1,000 mg/m2/day). Docetaxel-5-FU appears active in locally recurrent and/or metastatic SCCHN with acceptable toxicity at the dose of 5-FU 750 mg/m2.

A 45-year-old woman presented with a metastatic breast carcinoma and was treated with capecitabine, oral vinorelbine and trastuzumab combination therapy. The initial echocardiogram and the ECG were considered normal. She began treatment with 3-weekly cycles of the combination therapy. After the fourth dose of capecitabine, she presented with severe chest and arm pain, which was responsive to nitroglycerine spray. ECG at admission demonstrated tachycardia with ST-segment elevation suggesting ischemia. The clinical symptoms returned to baseline after a few hours and within 24 h the ECG showed inverted T in leads V3–V6. Cardiac ultrasonography revealed hypokinesia in the left ventricle without segmentary hypokinesia, with mildly reduced global systolic function, which normalized 1 week later. Two weeks later, she was rechallenged with capecitabine. After the fourth dose, the patient developed chest pain. ECG showed infero-apico-lateral injury, which normalized after administration of nitrates, nicorandil and verapamil and discontinuation of capecitabine. This case suggests that capecitabine can lead to the cardiotoxicity characteristic of other fluoropyrimidines. Therefore, it is important to inform patients about the risk of angina-like chest pain, to stop treatment immediately if symptoms occur, and to monitor the patient in hospital. Fluoropyrimidine rechallenge should be avoided because of the risk of ischemic event or sudden death.

Background Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination. Patients and methods We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0–2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H0) to 60% (H1); using the binomial exact method, 124 patients were required. Analyses were carried out in preplanned modified intention-to-treat (mITT) and per-protocol (PP) populations. Results Between November 2015 and November 2016, 127 patients were enrolled. Main grade III–IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1–53.6) in arm A and 26.7% (95% CI: 16.1–39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3–56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3–32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively. Conclusions The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment. Trial registration information EudraCT: 2014-004449-28: NCT: 0282701.

3531 Background: Conflicting results are reported for maintenance treatment with bevacizumab (bev) during chemotherapy free intervals (CFI) in metastatic colorectal cancer (mCRC). Methods: The objective was to compare the tumor control duration (TCD) by either bev maintenance (Arm A) or no treatment during CFI (Arm B) after induction chemotherapy (CT) (12 cycles of FOLFIRI + bev). CT was reintroduced at progression (8 cycles) and then a new CFI. The randomization was performed before induction CT. TCD was defined by the time between randomization and tumor progression during a CT sequence (Aparicio T et al, Dig Liver Dis, 2015). Per Protocol (PP) population was defined as patients (pts) with at least one CT reintroduction after first progression during CFI. We present the final analysis of the trial. Results: From March 2010 to July 2013, 491 pts were randomized. The median age was 64.6 years [range: 27 - 89], 64% of the pts were men, 93% of the pts were OMS 0-1 and 218 (44%) pts had a non-resected primary tumor. A progression during induction CT happen in 85 (17%) pts, 261 (53%) pts had at least one reintroduction, 107 (22%) pts had two and 51 (10%) pts had three or more re-introductions. Multivariate analysis in all pts revealed that WHO performance status ≥ 2, unresected primary tumor and BRAF mutation were associated with a shorter TCD. Unresected primary tumor and BRAF mutation were associated with a shorter overall survival (OS). Grade 3-4 toxicities were observed in 80% of the pts in arm A and 79% in arm B. Conclusions: The alternate irinotecan-based CT sequences with or without bev maintenance during CFI, revealed an impressive TCD. Bev maintenance monotherapy did not improved TCD, progression free survival (PFS) or OS. Clinical trial information: NCT00952029.Efficacy criteria. Arm A -Maintenance Median in months Arm B -No Maintenance Median in months HR [95% CI]; p-value All patients N = 246 N = 245 TCD 15.08 14.98 1.09 [0.87 - 1.37]; p = 0.43 PFS 9.20 8.90 0.92 [0.76,1.10]; p = 0.34 OS 21.65 21.98 1.05 [0.86,1.28]; p = 0.65 PP Population N = 124 (50%) N = 137 (56%) TCD 17.77 23.26 1.18 [0.87 ; 1.59]; p = 0.29 PFS 9.86 9.49 0.89 [0.69 ; 1.13]; p = 0.33 OS 27.47 28.58 1.09 [0.82 ; 1.45]; p = 0.56

Métastase surranélienne : survie après chirurgie d’exérèse M. Kapella, D. Genet, B. Pech de Laclause, S. Durand-Fontanier, M. Lachachi, A. Fabre, D. Valleix,B. Descottes Déterminer la survie après chirurgie d’une métastase surrénalienne apparue au cours de l’évolution des cancers extra surrénaliens. Étude rétrospective descriptive de 1995 à 2005. Étaient inclus les patients présentant une métastase surrénalienne apparue au cours d’une néoplasie primitive. Pour chaque patient étaient colligés l’âge de survenue, la néoplasie primitive, les circonstances de découverte clinique, les examens complémentaires contributifs, le type de métastase unique ou multiple, synchrone ou asynchrone de la néoplasie primitive, le délai d’apparition, la prise en charge et la survie en mois. La survie a été estimée par la méthode de Kaplan-Meier. Seize patients ont été inclus, 10 hommes et 6 femmes, l’âge moyen était de 55,5 ans (25 à 74 ans). Aucun signe clinique ne révèlait la métastase surrénalienne. Le scanner mettait en évidence la métastase surrénalienne dans 12 cas et dans 4 cas c’était le TEP scan. La néoplasie initiale était dans 6 cas un carcinome pulmonaire, dans 3 cas un carcinome rénal, dans 2 cas un mélanome, dans 2 cas un carcinome colorectal, dans 1 cas un carcinome œsophagien, dans 1 cas un carcinome pancréatique, dans 1 cas un lymphome B. Dans 9 cas la métastase surrénalienne était associée à d’autres localisations métastatiques, dans 7 cas elle était unique. Le délai d’apparition variait de 9 mois à 11 ans. Une chirurgie radicale a été réalisée dans 5 cas, une métastasectomie dans 10 cas et une biopsie seule dans un cas. La survie cumulée moyenne était de 12 mois avec des extrêmes de 2 à 120 mois. Elle était en moyenne de 8 mois lorsque la découverte de la métastase était synchrone au diagnostic de la lésion primitive. La médiane de survie après l’apparition d’une métastase surrénalienne a été de 12 mois. Lorsque la découverte de la métastase était synchrone au diagnostic de la lésion primitive la survie moyenne était de 8 mois. La prise en charge chirurgicale dépend de la néoplasie primitive et de son évolution métastatique globale. M. Kapella, D. Genet, B. Pech de Laclause, S. Durand-Fontanier, M. Lachachi, A. Fabre, D. Valleix,B. Descottes This study aims to determine the post-surgical survival after resection of adrenal metastasis from extra-adrenal primary cancers. A retrospective study of sixteen patients undergoing surgery for adrenal metastasis between 1995 and 2005 analyzed age, type of primary cancer, interval to detection of adrenal metastasis, type of surgery performed, and survival (Kaplan-Meier curve). The study included 10 men and 6 women with a mean age of 55.5 years (25-74). Adrenal metastasis causes no clinical signs or symptoms. Diagnosis was made on the basis of CT scan in 12 cases and PET scan in 4 cases. The primary cancer site was lung (6), kidney (3), melanoma (2), colorectum (2), esophagus (1), pancreas (1), and B-cell lymphoma (1). Metastasis was confined to the adrenal in 7 cases and associated with other-site metastasis in 9. The interval from diagnosis of the primary cancer to detection of the adrenal metastasis ranged from 9 months to 11 years. Surgery consisted of radical resection in 5 cases, metastasectomy in 10 cases, and biopsy in one case. The overall survival was 12 months (range 2-120 months); when the diagnosis of the metastasis was synchronous with that of the primary, survival was just 8 months. The survival after surgery for adrenal metastasis is poor; it is even more dismal when the metastasis is diagnosed synchronously with the primary tumor. Surgical management depends on the primary neoplasm and the extent of metastases.

3541 Background: AVEX study has demonstrated increased progression-free survival (PFS) with capecitabine + bevacizumab compared to capecitabine alone in pts aged over 70 with mCRC. The treatment with bevacizumab has so far not been evaluated in combination with other standard chemotherapy regimens for elderly pts. Methods: Pts aged 75 and over were randomly assigned in a 1:1 ratio to BEV-CT versus CT. Following regimens were authorized: LV5FU2, FOLFOX and FOLFIRI, chosen by the investigators. The primary endpoint, assessed 4 months after randomization was composite, based on efficacy: tumor control (stable disease or objective tumor response) and absence of decrease of the Spitzer QoL index and safety: absence of severe cardiovascular toxicities and unexpected hospitalization. The decision rules for the experimental arm were: if >15 pts met the efficacy criterion and if >25 pts met the safety criterion, the BEV-CT treatment is considered efficient and well tolerated. Results: 102 pts were randomized (51 BEV-CT and 51 CT arm), median age was 80 (range 75-91), men (55%), ECOG 0: 27%, 1: 53% and 2: 20%. CT was LV5FU2 in 53 pts (27 BEV-CT and 26 CT) and a doublet regimen in 49 pts (24 BEV-CT and 25 CT) including 23 FOLFOX and 26 FOLFIRI. Primary tumor was resected in 31 pts in BEV-CT and 30 pts in CT. Of the 46 pts evaluable in the BEV-CT arm, 23 pts (50% [90% CI: 37.1-62.9]) responded to the efficacy criterion and 28 pts (61% [90% CI: 47.7-73.0]) to the safety criterion. Multivariate analysis show that primary tumor resected and normal independent activity of daily living are predictive for the composite criterion. Conclusions: BEV-CT arm responded to the efficacy and safety criterion. Addition of bevacizumab to 1st line chemotherapy in pts aged over 75 years with a mCRC is efficient and well tolerated. Clinical trial information: NCT01417494.Preliminary follow-up results. CT BEV + CT Grade 3-5 toxicities 65% 80% Median time to autonomy failure in months (m) 5.5 [95% CI: 3.8-NA] 5.9 [95% CI: 3.8-14.8] Median time to QoL deterioration (m) 13.6 [95% CI: 11.6-NA] Not achieved Median PFS (m) 7.8 [95% CI: 6.6-10.6] 10.7 [95% CI: 8.2-13.8] Median overall survival (m) 19.7 [95% CI: 13.4-21.9] 21.7 [95% CI: 14.6-NA]

The aim of this study was to evaluate changes in the mode of discovery of breast cancer in the last 15 years. We compared two periods separated by a 10-year interval, during which a mass mammographic screening programme was established in our department.We made a retrospective comparison of the records of female patients with breast cancer diagnosed in our hospital over the period 1986-1989 (first period) and 1997-1999 (second period). The mass screening programme for breast cancer began in 1995.We collected 372 patients in the first period and 341 in the second. We found a significant change in the mode of the discovery of breast cancer between the two periods: 80.2% versus 51.9%, respectively, of the cases of breast cancer were discovered by breast self-examination, 10.2% versus 13.7% were discovered by a physician, and 4.8% versus 29.1% were discovered by routine mammography as part of an individual or mass screening programme. The mean size of the tumours decreased significantly (2.6 cm versus 2.3 cm: p = 0.019), and the number of tumours with initial metastases or lymph node involvement decreased, almost attaining the level of significance (p = 0.06). It is difficult to compare the survival and disease-free survival curves because of the short follow-up in the second period (median follow-up = 10 months). However, a marked difference appears to be developing (p < 0.0001): patients diagnosed by mammography are showing better survival and disease-free survival compared with the others.We observed that more widespread use of mammography screening for breast cancer led to smaller tumours being discovered during the second period, with less lymph node involvement and less initial metastasis. Breast cancer screening is one of the most intensively evaluated health care practices with eight completed randomized trials yet its net benefit has remained controversial. It has been shown that, at least for patients aged 50 to 70, properly organized mass screening for breast cancer led to a reduction in mortality rate. However, individual breast self-exam, physician and mammographic screening can interfere with assessment of mass screening programmes in terms of individual benefit. In addition, introducing a mass screening programme may induce opportunistic screening in non-invited age groups and influence health behaviour in the target and non target populations. A retrospective study was performed to evaluate the mode of discovery, the diagnostic presentation, and prognostic factors in breast cancer in a French department before and after initiation of a mass-screening programme (MSP).

Implanted venous access devices (IVAD) are routinely used in oncologic patients. Thrombotic complication is a source of morbidity. During one year 246 patients with different solid neoplastic diseases received IVAD for chemotherapy administration. Two hundred forty-nine IVAD were placed percutaneously or by surgical cutdown. IVAD were flushed immediately after implantation with 3-5 mL of heparinized saline (100 U/mL). No monthly flush was required. A prospective evaluation of thrombotic complications was realised. in event of catheter dysfunction and/or clinical symptoms of phlebitis, a catheter opacification and/or a Doppler ultrasonography were performed. Twenty-three catheter dysfunctions were noted, corresponding to 13 catheter occlusions. Twelve patients presented clinical symptoms of phlebitis. Eleven venous thrombosis were diagnosed in this group; 10 by echo-Doppler and one by scanography. A unvaried statistic analysis using Fisher's test was performed to detect risk factors. Two factors were identified: the position of catheter tip above T4 (p < 0.001) and mediastinal or cervical lymph nodes larger than 6 cm (p < 0.001). The first increased the risk of catheter occlusion and the second increased the risk of phlebitis.

3534Background: Bevacizumab (Bev) is widely used in mCRC but there is no validated predictive factor. Several studies have reported the impact of SNPs in the Vascular Endothelial Growth Factor-A (V...

Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab.We evaluated the impact of SNPs of VEGF-A, VEGF receptors (VEGFR-1, VEGFR-2), and hypoxia inducible factor-1α (HIF-1α) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI).We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451).In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype (n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7-17.1)] (p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1-42.8) versus 22.5 (95% CI: 18.6-24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2-11.3) versus 9.2 (95% CI: 8.71-10.1)], and duration of the first CFI [4.6 (95% CI: 1.6-13.3) versus 4.14 (95% CI: 0.5-29.0) months, p = 0.3].Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.

A review of the literarure indicates that there are two essential prognostic factors in stage Ib cancer of the cervix: the size of the tumour (determined by a physical examination and MRI) and invasion of the lymph nodes (determined by lymphadenectomy). Of the available means of treatment, many workers use surgery at stage Ib1 and a combination of chemotherapy and radiotherapy at stage Ib2. Hence, our pre-therapeutic assessment usually includes a physical examination under general anaesthesia, MRI of the abdomen and pelvis, and laparoscopic pelvic lymphadenectomy for stage Ib1 and laparoscopic lumbo-aortic lymphadenectomy for stage Ib2. For stage Ib1 < 2 cm, if extemporaneous examination of the pelvic lymph nodes is positive, we perform lymphadenectomy of the lumbo-aortic lymph nodes and initiate treatment with chemotherapy and radiotherapy. If pelvic lymphadenectomy gives negative results in a woman who does not wish to remain fertile, we carry out radical vaginal hysterectomy (Schauta-Stoeckel) rather than radical hysterectomy (Piver 2) by laparotomy or laparoscopy. If the margins are healthy and devoid of vascular or lymphatic involvement, no further treatment is given. If this is not the case, we suggest a postoperative radio-chemotherapy. For patients who wish to retain their fertility, we carry out radical cervicectomy. For tumours measuring between 2 and 4 cm, and if pelvic lymphadenectomy is positive, we propose radio-chemotherapy, or radical hysterectomy as for small tumours. For Ib2 tumours, and if no lumbar adenopathy is seen at MRI, we perform a lumbo-aortic lymphadenectomy, followed by a radio-chemotherapy. If invasion of lumbar lymph nodes is suspected at MRI, we perform a biopsy on the left scalenic lymph nodes; if invasion is present at this level, we give palliative treatment with simple pelvic radiotherapy. If lumbo-aortic lymphadenectomy reveals invasion, radiotherapy is directed at these nodes. If, at the end of combined chemotherapy and radiotherapy, some remaining tumour is discovered at the MRI assessment, we carry out extrafacial hysterectomy.

The purpose of this study was to evaluate the efficacy of concurrent chemotherapy and irradiation in inflammatory breast cancer (IBC). Between January 1990 and December 1998, forty-eight non-metastatic patients with clinical or occult IBC were treated with chemotherapy and irradiation. The induction chemotherapy consisted of epirubicin, cyclophosphamide and vindesin, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and 6 cycles of epirubicin, cyclophosphamide and fluorouracil Hormonal treatment was given routinely but mastectomies were not routinely performed. A high rate of locoregional control was obtained in 47 evaluable patients of whom 93.6 % achieved a complete clinical response. Three patients had locoregional relapses, always with concomitant metastatic dissemination. In 47 patients, 21 developed metastatic dissemination with a median delay of 23 months. Median disease-free survival (DFS) was 45 months. Median overall survival (OS) has not yet been reached after a median follow-up of 44.5 months. The 3-year DFS rate was 53 % and the 3-year OS rate was 71 %. Toxicity was mainly hematological. During the induction therapy, grade 3 or 4 neutropenia occurred in 54 % of patients, grade 3 or 4 thrombocytopenia in 23 % and grade 3 or 4 anemia in 8 %. The administration of induction chemotherapy and concomitant irradiation is feasible in patients with IBC. The hematological toxicity of this treatment approach is significant but nevertheless, the treatment achieves a high degree of locoregional control and improved survivaL

Abstract DNA topoisomerase I (Topo I) is involved in DNA replication, transcription, recombination and repair. Clinical interest has focused on Topo I as it is the molecular target of camptothecin (CPT), used in first and second lines of treatment for different cancer types. Furthermore, it is well demonstrated that the patients who best responded to CPT-based chemotherapy were generally those with the greatest tumoral Topo I expression and/or activity. We developed a sensitive, simple and reproducible method to measure Topo I mRNA expression in human cancer samples. Experiments were performed in two steps. First, we checked the accuracy of the reverse transcription-polymerase chain reaction (RT-PCR) method by testing intra- and interassay reproducibility of

The aim of this work was to evaluate the value of contrast enhanced MRI for determination of response to neoadjuvant chemotherapy (type FEC) in breast cancer according to two parameters: size of the enhancing tumor and the maximum relative enhancement curve (MRC) in the same tumor area. Twenty women with breast cancer (15 invasive ductal carcinomas and 5 invasive lobular carcinomas) T2 (n = 8) or T3 (n = 12) were evaluated by physical examination and MRI after a minimal of three courses of FEC and prior to surgery. Data from physical examination and imaging studies were compared to histopathological findings. Physical examination estimated correctly the residual tumor size in 45% of cases and MRI in 60% with 3 false negative cases. Among evaluated patients with MRI measurable residual tumor, tumor size was underestimated in 69% of the cases and overestimated in 31% of the cases. A MRC flattening was observed in 5 cases among the patients with a partial response or clinical stable disease correlated with a poor cellular density in the microscopic findings. MRI monitoring of chemotherapy response can be useful for guiding surgery. Therefore, underestimation of the residual tumor size and false negative rate are remaining problems.

In some situations, there is a need for rapid mutation tests for guiding clinical decisions and starting targeted therapies with minimal delays. In this study we evaluated the turnaround time before and after the implementation of a fully automated multiplex assay for KRAS and NRAS/BRAF mutation tests (Idylla™ platform, Biocartis) in metastatic colorectal cancer. The objective of this project was to compare the turnaround times in 2017–2018 with the fully automated multiplex assay to the 2016 results with previous methods. Centers with a number of tests for metastatic colorectal cancer > 100 yearly and a usual turnaround time ≥ 3 weeks for mutation detection were selected. Results of 505 KRAS tests and 369 NRAS/BRAF tests were transmitted by 10 centers. The mean turnaround time from test prescription to reception of results was reduced from 25.8 days in 2016 to 4.5 days in 2017–2018. In conclusion, this pilot project shows that the Idylla™ platform for testing KRAS and NRAS/BRAF mutations allows an optimized turnaround time from test prescription to reception of results.

The COVID-19 pandemic has dramatically changed the Health Care System organization in many European countries. Many Oncology departments have rapidly implemented telehealth in their clinical practice. For breast cancer (BC) patients (pts), up to 80% of all in-person visits have been transformed in TV.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66 years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand-foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3-7.6) and 2.8 months (95% CI: 2.6-3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

ABSTRACT Aim: The FOLFIRI + bevacizumab (bev) regimen is a standard 1st-line chemotherapy (CT) in metastatic colorectal cancer (mCRC). Several trials have evaluated chemotherapy-free intervals (CFI) with the aim of prevening patients (pts) from experiencing toxicities, with conflicting results. Methods: This study aimed to compare the tumour control duration (TCD) by a 1st-line CT followed by either bev maintenance (Arm A) or no treatment during CFI (Arm B). Both arms start with 12 cycles of induction CT of FOLFIRI + bev; then a CFI is made until progression. CT is reintroduced at progression, for a 8 further cycles; then a new CFI is put in place and so on. The TCD is defined by the time between randomization and strategy failure corresponding to tumour progression during a FOLFIRI + bev sequence. It was expected that bev maintenance will extend TCD from 10 to 14 months. We present the results of the planned interim analysis (IA) after 203 events were observed. Results: 494 pts were enrolled from March 2010 to July 2013. The IA was performed on the data of 490 pts (245 in both arms). The median age was 64.5 years; 218 (44%) pts had a non-resected primary tumour. During induction CT, 68% of the pts received the 12 planned cycles. At the time of analysis, 60% of the pts received only the 1st sequence of FOLFIRI + bev, and 29% received 2 sequences. The median TCD was 14.3 months in arm A and 13.4 months in arm B (HR = 0.98, p = 0.86). The estimated progression free survival (PFS) was 9.2 months [8.2; 9.7] in arm A and 8.0 months [7.7; 9.0] in arm B. The median overall survival was not met. Grade 3-4 toxicities were observed in 74% of the pts in arm A and 71% in arm B. No safety issue was detected based on the serious adverse events (SAE). Conclusions: The strategy evaluated in PRODIGE 9, to alternate CT sequences with or without bev maintenance during CFI, revealed an impressive TCD in both groups and longer than expected in arm B. The IA shows no significant improvement of TCD with bev maintenance therapy. A trend to a PFS improvement is observed in the bev maintenance arm that should be confirmed by the final analysis planned in 2015. No increase in toxicity was observed in the bev maintenance arm. This study validates the concept of a chemo re-introduction strategy with irinotecan-based regimen in first-line mCRC. Disclosure: T. Aparicio: Roche, Sanofi, Merck, Novartis; J. Bennouna: Roche; J. Taieb: Roche; O. Bouche: Roche; J. Phelip: Roche. All other authors have declared no conflicts of interest.

Aim: TG4010 immunotherapy product is a poxvirus (MVA) coding for MUC1tumor-associated antigen and interleukin-2. Previous Phase 2 trials have demonstrated the safety and efficacy of TG4010 in combination with chemotherapy for the treatment of advanced NSCLC. In addition, a previous study showed that a normal level of Triple Positive Activated Lymphocytes (TrPAL, CD16 + CD56 + CD69+) at baseline might be a predictive biomarker for TG4010 efficacy.

In 1st-line trials, the relative Progression Free Survival (PFS) benefit of adding CDK4/6 inhibitors to AI was consistent across all subgroups of patients (pts), including those with lower ER expression. However, little is known about the absolute PFS obtained under CDK4/6i and AI in pts with low ER expression and whether PR and HER2 expression impact PFS in this setting. PADA-1 is a phase III trial (NCT03079011) testing the clinical utility of ESR1mut detection in blood in ER ≥ 10% HER2- MBC pts receiving 1st- line Pal + AI. We investigated the association of locally-assessed ER (%), PR (%) and HER2 (0,1+,2+) IHC expression on the most recent tumor sample with PFS under Pal + AI. Of 1017 pts, 12 (1.2%), 34 (3.5%), 181 (18.5%) & 751 (76.8%) had an ER% expression of [10-20%], [21-50%], [51-80%] & [81-100%], respectively. N=249 pts (29.2%), 148 (17.3%), 186 (21.8%) & 270 (31.6%) had a PR% of [0-20%], [21-50%], [51-80%] & [81-100%], respectively (Allred scores will be presented). Available HER2 IHC scores were 0 & 1+/2+ in 357 (54.6%) & 296 (45.4%) pts, respectively. In univariate analysis, after a mFU of 28.1 months and 527 PFS events (51.8%) under Pal + AI, mPFS in pts with [10-50%], [51-80%] & [81-100%] ER IHC were 14.1, 21.6 & 30.1 months, respectively. mPFS in pts with [0-50%], [51-80%] & [81-100%] PR IHC were 20.6, 27.1 and 42.6 months, respectively. Longer PFS were observed in HER2(1/2+) vs (0) MBC (HR=0.79 [0.64;0.98]). In multivariate analysis, aside standard prognostic factors (PS, age, visceral disease, number of metastatic site, DMFI), both ER% and PR% had an independent prognostic impact: each +10% gain in ER% was associated with a reduced 10% risk of PFS event under Pal + AI (HR=0.90, 95%CI [0.84;0.96], p=0.002); each +10% gain in PR% was associated with a reduced 8% risk of PFS event under Pal + AI (HR=0.92, 95%CI [0.90;0.95], p<0.001). ER and PR IHC % have significant, independent and similar impact on PFS achieved under 1st line by Pal + AI. The 14.1 months absolute mPFS obtained among pts with ER IHC <50% suggests that CDK4/6i + AI remains a good treatment option in this patient population.

The purpose of this work was to determine the response rate and toxicity of a combination of Carmustine and Cisplatin administered before radiation in patients with newly diagnosed high grade astrocytoma. A good response rate has been published with this association in primary cerebral high grade tumor. This protocol was administered in a homogeneous population of 37 adult patients with measurable tumor on magnetic resonance imaging (MRI) or CT scan. After biopsy or subtotal resection, the patients received BCNU 40 mg/m2/d and CODP 40 mg/m2/d, for 3 days every 28 days for 3 cycles. Evaluation was performed before each cycle. Radiation therapy began 4 weeks after completing the chemotherapy or immediately if there was evidence of tumor progression on chemotherapy. Seven out of 37 (19%) demonstrated tumor regression with a median duration to progression of 11 months. Median survival was 6 months. Myelosuppression was the predominant but manageable toxicity. This work indicated that the first chemotherapy protocol gave poor results in a homogeneous group of patients, with bad prognosis.

4117 Background: Tolerability and activity of 5-day (d) infusional FU-oxaliplatin were improved with Chrono as compared with Cst in colorectal cancer pts(Lévi et al, Lancet 1997). CDDP addition to FU tended to prolong Progression-Free Survival (PFS) in pancreatic cancer pts(Ducreux et al, Ann Oncol 2002). Methods: A factorial design tested the relative effects of CDDP addition (100 mg/m2/course, c) to FU (c1/c2/c3 : 5/6/6.5 g/m2) and Cst vs Chrono (FU : 10 pm-10 am, peak at 4 am; CDDP : 10 am-10 pm, peak at 4 pm) 5 d q21d. Pts with advanced (25) or M (82) histologically-proven pancreatic cancer were registered in 15 centers. CTC toxicity was assessed q10 d and response q 3c. Survival was the main endpoint. Results: Characteristics : CDDP no/yes, 55/52 pts; Chrono no/yes, 54/53 pts; median age, 63 y; WHO PS 0/1/2, 35/52/20 pts; M sites 0/1/2+, 16/51/36 pts. CDDP increased median PFS from 2.1 months (mo.) [95% CL, 1.9–2.3] to 3.2 mo. [2.5–5.0] and median survival from 5.4 mo. [3.9–8.4] to 8.3 mo. [5.7–11.9]. Median survival (mo.) was 6.1 on Cstand 6.7 on Chrono(NS). CDDP addition reduced the risk of P by 44% (Log rank, p = 0.005) and that of death by 20% (p = 0.26). CDDP significantly increased grade 3–4 toxicity per patient : neutropenia (58 vs 6%), thrombopenia (38 vs 2%), anemia (25 vs 12%). The dose intensities of FU and CDDP were higher with Chrono (p = 0.03). Despite this, Chrono decreased the incidence of grade 3–4 mucositis (8 vs 27%, p = 0.01), anorexia (10 vs 23%) and diarrhea (2 vs 10%). Conclusions: CDDP addition to FU near maximum tolerated doses prolonged PFS in pancreatic cancer pts, with a trend toward improved survival. Chronoameliorated non haematological tolerability and allowed to administer higher DIs. Chrono FU should be combined with a less toxic Pt complex to concurrently improve antitumor efficacy and tolerability in M pancreatic cancer. Support: NCI, ARC (grant 9033), ARTBC, hôp. P Brousse, Villejuif (F). No significant financial relationships to disclose.

ABSTRACT Background Whether an anticoagulant prophylaxis is needed for patients with cancer with a central venous catheter is a highly controversial subject. We designed a study to compare different prophylactic strategies over 3 months of treatment. Patients and methods: We performed a phase III prospective, randomized trial. After the insertion of a central venous access device, consecutive outpatients with local nodes or metastatic invasion, and planned chemotherapy were randomized to no anticoagulant prophylaxis, low molecular weight heparin (LMWH : dalteparine 2500 IU, nadroparine 2850 IU, or enoxaparine 4000 IU, once daily), or warfarin 1 mg/day. Treatments were given over the first 3 months. Doppler ultrasound and venographies were performed on days 1 and 90 or sooner in case of clinical presumption of thrombosis. Results A total of 420 patients were randomized and 407 were evaluable. Forty-two catheter-related deep-vein thromboses (DVT) occurred (10.3%), 20 in those with no anticoagulation, 8 in those receiving warfarin, and 14 in those receiving LMWH. Anticoagulation significantly reduced the incidence of catheter-related DVT (P = 0.035), with no difference between warfarin and LMWH. The most frequent DVT localization was at the distal extremity of the catheter in the superior vena cava (50%). The mean delay of occurrence was 30 days, and 30 were asymptomatic (71%). Anticoagulation use also had an impact on unrelated-cathter DVT (P = 0.007 by Fisher's test on the 9 events) with no difference between warfarin and LMWH use (0.75 versus 0.72%, P = 1). Safety was good. One hundred forty six patients experienced thrombopenia, but only 24 were grade 3 or 4, chemotherapy-induced, increased by anticoagulant use (p  Conclusions Prophylaxis showed a benefit regarding catheter-related and non catheter-related DVT with no increase in serious side effects. Disclosure All authors have declared no conflicts of interest.

2066 Background: Chronotherapy is an aim to increase efficacy/toxicity ratio. Objectives: to define the dosing least toxic time (DLTT) of V (30 mg/m 2 /d at D1 and D6), combined with chrono 5-FU (10 pm-10 am) (850 mg/m 2 D2-D5) over 3 courses q3w. Methods: A logistic regression model (LRM) estimated the DLTT assuming a sinusoidal distribution over time (i.e. over the 8 different arms) of the toxicity rate observed in each arm. The associated 90% confidence limits (CL) has been obtained by bootstrap method. Results: 90 patients were recruited. Toxicity in 46 pts led to the V dosage reduction to 25 mg/m 2 /d. 40 and 43 pts were assigned the V30 and the V25 regimen. 12% pts went off for toxicity, 5% for PD, 1% for refusal, 1% for unrelated death. 224 cycles were analyzed . V and 5FU relative dose intensities were 79.4% and 78.2% in the V30 while 88.1% and 87.4% in the V25 pts. Over the 3 cycles, toxicity by cycle was: Grade (G) 3 and G4 leucopenia in 47% and 29%, G3 and G4 neutropenia in 12% and 77%. G3 febrile neutropenia in 34%. G2 thrombopenia and anemia in 4% each. Other G3 and G 4 toxicity were stomatitis (12%), alopecia (7%), and less than 5%: cardiovascular, lethargy, diarrhea, constipation, other gastrointestinal, infection, sensory, pulmonary. LRM could not demonstrate a DLTT for the neutropenia G3–4 incidence, the primary endpoint. However, based on the stratified by dose analysis, a 90% CI of less than 6 hours width was observed: - around 17H17 [14H04–20H03] for the incidence of leucopenia G3–4. - around 8H16 [06H04–10H39] for tolerability (dose reduction, dose delay or treatment interruption for toxicity reason). This suggests that treatment tolerability was influenced by other factors beside leucopenia nadir. No other 90% CI of less than 6 hours width could be observed for other toxicity endpoints. Conclusions: Using a novel time finding study design with ad hoc statistics, this first randomized multicenter study has determined a DLTT for Vinorelbine in 90 women with MBC. Additional studies are ongoing to further assess the relevance of this trial design method that could prove useful for improving the safety of anticancer drugs during their clinical development. Support Pierre Fabre Oncology, Ligue Bourguignonne contre le Cancer No significant financial relationships to disclose.

Although anti-EGFR monoclonal antibodies are active as single-agent therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), few studies are available on their role in maintenance therapy during chemotherapy (CT)-free intervals (CFI). RAS wt unresectable mCRC patients with controlled disease after FOLFIRI + cetuximab (8 cycles) were randomized (1:1) to receive maintenance with bi-weekly cetuximab alone (arm A) or observation (arm B) until disease progression (PD)/unacceptable toxicity/death. Randomization was stratified according to tumor response, center, baseline Köhne score, CEA and platelet count. In case of tumor progression during the CFI, FOLFIRI + cetuximab was to be reintroduced for 8 cycles, followed by a new CFI. The primary objective of this multicenter non-comparative randomized phase II trial was the 6-month progression-free rate (PFR) after initiation of maintenance therapy. A total of 134 randomized and evaluable patients (67 per arm) were required (Fleming’s one-step design, one-sided α=5%, β=20%, H0: 40%; H1: 55%). Among secondary endpoints, overall response rate (ORR) and progression-free survival (PFS) from randomization are available. RAS and BRAF status were centrally validated by NGS using the AmpliSeq™ Colon and Lung Panel v2. 214 patients were included according to RAS status locally assessed in each center, and 139 randomized (67 arm A/72 arm B). Baseline characteristics were: median age, 64/68 years; ECOG PS 0, 55%/49%; single metastatic site, 58%/47%; right-sided primary, 24%/18%. The median follow-up was 29.6 months.Table: 429PResults according to RAS and BRAF statusIncludedRandomizedArm A - cetuximabArm B - ObservationAll n=214BRAFV600E+RASwt n=184 (86%)All n=67BRAFV600E+RASwt n=60 (90%)All n=72BRAFV600E+RASwt n=66 (92%)ORR (%) before randomization5558757869686-month PFR (%) after randomization [95% CI]--39 [27; 52]42 [29; 55]7 [2; 16]8 [3; 17]Median PFS (months) after randomization [95% CI]--5.3 [3.7; 7.4]5.7 [3.7; 7.7]2.0 [1.8; 2.4]2.0 [1.8; 2.7] Open table in a new tab Although the cetuximab maintenance arm did not meet the primary objective, a clinically meaningful difference in PFS in favor of cetuximab maintenance was found in RAS/BRAF wt mCRC patients.

4117 Background: Tolerability and activity of 5-day (d) infusional FU-oxaliplatin were improved with Chrono as compared with Cst in colorectal cancer pts(Lévi et al, Lancet 1997). CDDP addition to FU tended to prolong Progression-Free Survival (PFS) in pancreatic cancer pts(Ducreux et al, Ann Oncol 2002). Methods: A factorial design tested the relative effects of CDDP addition (100 mg/m2/course, c) to FU (c1/c2/c3 : 5/6/6.5 g/m2) and Cst vs Chrono (FU : 10 pm-10 am, peak at 4 am; CDDP : 10 am-10 pm, peak at 4 pm) 5 d q21d. Pts with advanced (25) or M (82) histologically-proven pancreatic cancer were registered in 15 centers. CTC toxicity was assessed q10 d and response q 3c. Survival was the main endpoint. Results: Characteristics : CDDP no/yes, 55/52 pts; Chrono no/yes, 54/53 pts; median age, 63 y; WHO PS 0/1/2, 35/52/20 pts; M sites 0/1/2+, 16/51/36 pts. CDDP increased median PFS from 2.1 months (mo.) [95% CL, 1.9–2.3] to 3.2 mo. [2.5–5.0] and median survival from 5.4 mo. [3.9–8.4] to 8.3 mo. [5.7–11.9]. Median survival (mo.) was 6.1 on Cstand 6.7 on Chrono(NS). CDDP addition reduced the risk of P by 44% (Log rank, p = 0.005) and that of death by 20% (p = 0.26). CDDP significantly increased grade 3–4 toxicity per patient : neutropenia (58 vs 6%), thrombopenia (38 vs 2%), anemia (25 vs 12%). The dose intensities of FU and CDDP were higher with Chrono (p = 0.03). Despite this, Chrono decreased the incidence of grade 3–4 mucositis (8 vs 27%, p = 0.01), anorexia (10 vs 23%) and diarrhea (2 vs 10%). Conclusions: CDDP addition to FU near maximum tolerated doses prolonged PFS in pancreatic cancer pts, with a trend toward improved survival. Chronoameliorated non haematological tolerability and allowed to administer higher DIs. Chrono FU should be combined with a less toxic Pt complex to concurrently improve antitumor efficacy and tolerability in M pancreatic cancer. Support: NCI, ARC (grant 9033), ARTBC, hôp. P Brousse, Villejuif (F). No significant financial relationships to disclose.

For a selective excitation of spin-flip strength, (6Li,6He) reactions can be a useful tool, because: a) 6Li and 6He have ground-state spin and parity values Jπ = 1+ and 0+, respectively; b) 6He has no particle-stable excited state, thus effects from ejectile excitation can be avoided. The (6Li,6He) experiments were performed at 100 MeV/nucleon, at which incident energy the reaction is expected to be single-step dominant. Through the analysis of the good-resolution (6Li,6He) data on 13C, 26Mg, 27Al and 58Ni targets, the evidence for a proportional relationship between 0° cross sections and the corresponding Gamow-Teller transition strengths is examined. Suppression of non-spin flip excitations is discussed based on the hindrance of the excitation of the isobaric analog state.

PRODIGE 20 randomized patients (pts) aged 75+ to receive bevacizumab + chemotherapy (LV5FU2, FOLFOX, FOLFIRI, according investigators choice) or chemotherapy alone. The primary endpoint based on efficacy and safety was reached in BEV-CT. This analysis presents updated progression-free survival (PFS) and overall survival (OS), including univariate and multivariate analyses. PFS was defined as time from randomization to progression or death and OS as time from randomization to death. Prognostic factors analyzed were: treatment arm, age (≤80 vs >80), sex, rectum vs colon, primary tumor resected or not, doublet vs mono-chemotherapy, body mass index (≥21 vs <21), Spitzer QoL (≤7 vs 8-10), MNA-SF (≥11 vs <11), G8 (>14 vs ≤14), ADL (6 vs <6), IADL (14 vs <14), mini-COG (positive vs negative), GDS (≥1 vs 0), presence of a caregiver, hospitalization in the 12 months previous randomization, energy testing (<5 vs ≥5), aging risk factor questionnaire (>2 vs ≤2), fall in the 6 months previous randomization or one-leg balance, presence of anemia, albumin (>35 vs ≤35 g/L), creatinine clearance (>45 vs ≤45 mL/min), CEA (>2N vs ≤2N), CA19.9 (>2N vs ≤2N) and Köhne criteria (low vs intermediate vs high). Baseline variables significant at 15% in univariate analysis were introduced in the multivariate Cox model. 102 pts were randomized (51 BEV-CT, 51 CT) and 100 pts were treated: chemotherapy was LV5FU2 in 52 pts (26 BEV-CT, 26 CT) and a doublet regimen in 48 pts (23 BEV-CT, 25 CT) including 23 FOLFOX and 25 FOLFIRI. The median follow-up was 20.4 months. 25 pts BEV-CT and 31 pts CT received 2nde line chemotherapy. Multivariate analysis shows that Spitzer QoL, albumin and Köhne criteria were prognostic for OS. Spitzer QoL and Köhne criteria were also prognostic for PFS.Tabled 1CT [95% CI]BEV + CT [95% CI]Median PFS (m)7.8 [6.6-10.2]9.7 [8.2-12.0]12 months PFS rate23.5% [13.0-35.8]37.3% [24.3-50.2]Median OS (m)19.8 [13.9-23.7]21.7 [14.8-30.3]36 months OS rate10.1% [3.1-22.0]27.0% [15.7-39.7] Open table in a new tab Spitzer QoL and Köhne criteria are prognostic factors for OS and PFS and should be used as stratification factors in future trials in elderly pts. Pts with a prolonged OS were observed in BEV-CT.

The western North Atlantic population of right whales (Eubalaena glacialis) is one of the most critically endangered of any whale population in the world. Among the factors considered to have potentially adverse effects on the health and reproduction of E. glacialis are biotoxins produced by certain microalgae responsible for causing harmful algal blooms. The worldwide incidence of these events has continued to increase dramatically over the past several decades and is expected to remain problematic under predicted climate change scenarios. Previous investigations have demonstrated that N. Atlantic right whales are being exposed to at least two classes of algal-produced environmental neurotoxins—paralytic shellfish toxins (PSTs) and domoic acid (DA). Our primary aims during this six-year study (2001–2006) were to assess whether the whales’ exposure to these algal biotoxins occurred annually over multiple years, and to what extent individual whales were exposed repeatedly and/or concurrently to one or both toxin classes. Approximately 140 right whale fecal samples obtained across multiple habitats in the western N. Atlantic were analyzed for PSTs and DA. About 40% of these samples were attributed to individual whales in the North Atlantic Right Whale Catalog, permitting analysis of biotoxin exposure according to sex, age class, and reproductive status/history. Our findings demonstrate clearly that right whales are being exposed to both of these algal biotoxins on virtually an annual basis in multiple habitats for periods of up to six months (April through September), with similar exposure rates for females and males (PSTs: ∼70–80%; DA: ∼25–30%). Notably, only one of 14 lactating females sampled did not contain either PSTs or DA, suggesting the potential for maternal toxin transfer and possible effects on neonatal animals. Moreover, 22% of the fecal samples tested for PSTs and DA showed concurrent exposure to both neurotoxins, leading to questions of interactive effects. Targeted studies employing both in vivo and in vitro model systems represent the next logical step in assessing how and to what extent these algal biotoxins might compromise the health and reproduction of this endangered population.

TPS1116 Background: PARP inhibitors have documented clinical activity in patients with HER2 negative breast cancer (BC) and a germline pathogenic variant (PV) in BRCA1 or BRCA2. Defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI) have been associated with preclinical cellular sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested synergy between immune checkpoint blockade and PARP inhibitors. Indeed, tumors with deficiency in HRR have higher mutagenic potential and produce a larger number of neoantigens. Around 60% of BC with a germline PV in BRCA1/ 2 are ER+/HER2- tumors, and the ER-pathway remains a key target of their therapy. The combination of PARP inhibitors with endocrine therapy has shown to be superior to monotherapy. Methods: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab in ER+/HER2- metastatic or locally advanced BC with somatic or germline PV in BRCA1, BRCA2 or other genes implicated in the HRR pathway (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes ( AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor NGS. Further an amendment in May 2021, patients with only alterations in these other actionable genes can no longer be included. Patients must have received 1 prior line of endocrine therapy for their metastatic BC, including CDK4/6 inhibitor and maximum of 1 line of chemotherapy in the metastatic setting. Patients receive olaparib (twice daily at 300 mg), fulvestrant (2 intramuscular injections of 250 mg every 28 days) and durvalumab (1500 mg intravenous every 4 weeks). The primary objective is to evaluate the progression-free survival rate at 24 weeks. Secondary endpoints include safety, overall survival, objective response rate, in the overall population and in the germline BRCA mutated population. With an optimum two-stage Simon design, α = 2.5%, β = 5%, p0 (probability of inefficiency maximum) = 50%, p1 (probability of minimum efficiency) = 65%, it is necessary to include 158 patients. The strategy could be considered sufficiently effective if there are at least 87 patients without progression at 24 weeks. Given the lack of safety data from this association, a safety run-in phase including 6 patients has been completed without DLT. As of December 31, 2021, 266 patients have been screened of whom 102 have been treated. The first interim analysis occured in November 2021 after the inclusion of 64 evaluable patients. IDMC suggested that the trial continue as planned. Clinical trial information: NCT04053322.

which was significantly higher in frail patients (ANOVA test). At 3 months the objective clinical response to the assigned treatment was: 3 PR, 4 SD and 3 PD for ‘fit’ patients; 5 PR, 11 SD and 7 PD for ‘intermediate’ patients; 5 PR, 5 SD and 8 PD for ‘frail’ patients. Overall, the ORR was 25.5% and the median survival was 7.9 months; 36 out of 51 patients are alive. Thirty-two patients also completed 6 months of therapy: 8 were ‘fit’, 15 ‘intermediate’ and 9 ‘frail’. As for the correlation of CGA categories with treatment and clinical outcome, no difference was found in the clinical outcome variables after 3 months of treatment (ANOVA test), although a trend toward a better clinical response for fit patients was observed. The study is still in progress: the required accrual is at least 32 patients for each CGA category. The CGA assessment is strongly recommended as an essential component of the clinical evaluation of elderly patients. Large prospective clinical trials in this field are awaited.

We have carried out a phase II study to evaluate the efficacy and the toxicity associated with the combination of gemcitabine, ifosfamide, and cisplatin (GIP) in chemotherapy-naive patients with advanced nonsmall cell lung cancer (NSCLC).Each cycle consisted of treatment with ifosfamide (3000 mg/m2) and gemcitabine (1500 mg/m2) on day 1, followed by cisplatin (100 mg/m2) and gemcitabine (1500 mg/m2) on day 15. Each treatment cycle was repeated every 28 days. A maximum of 6 cycles were administered.Sixty NSCLC patients (23 stage III and 37 stage IV) were entered in this study. The median survival for all patients is 9 months (stage III: 12.3 months; stage IV: 7.5 months). The overall survival at 1 and 2 years is 38% and 17%, respectively (52% and 30% for stage III; 30% and 8% for stage IV). The median time to progression is 6.3 months (stage III: 8.8 months; stage IV: 3.6 months). Progression free survival at 1 and 2 years for all patients is 22% and 8%. The response rate is 56% for patients with stage III disease and 27% for patients with stage IV disease. Among the grade 3/4 toxicities, hematological toxicity was the most frequent (59% of patients) followed by gastrointestinal toxicity (nausea/vomiting) in 21% of patients.The GIP combination yields an efficacy, in terms of response and survival, comparable to that reported with other triplet combination treatments for local advanced or metastatic NSCLC, with an acceptable toxicity profile.

Several genes have been involved in drug resistance but none are currently used in the drug decision process. To address this problem, mRNA levels were measured for the 5-fluorouracil metabolism-related genes, thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumor samples of 40 patients with synchronous metastatic colon cancer by quantitative RT-PCR. Drug response and overall survival were also obtained for each patient. A logistic regression model was defined to calculate a response predicting score (RPS) with gene expression levels. This RPS split responders from non- responders as, at the best statistical threshold (0.35), the area of receiver operating characteristic (ROC) curve established with this method was 0.82 and sensitivity and specificity were respectively 100 % and 65.4 %. Furthermore patients with scores above 0.35 tended to have better overall survival than those with a score less than 0.35 (p=0.09). Colorectal cancer is the second most common cancer in developed countries and is diagnosed at a metastatic stage in 20% of all cases (1). Several genes have been suspected to play a role in resistance to chemotherapy drugs (2), the most cited for 5-fluorouracil (5-FU) are thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) but many more have been implicated (3, 4). A metaanalysis showed that TS seems to confer a hazard ratio of 1.74 for overall survival (OS) and that RT- PCR methods quite consistently give a positive link between TS overexpression and negative drug response (5). Nevertheless, the usefulness of these markers, including TS, is still questionable as the thresholds or cut-off values are difficult to define and the decision to select one drug over another based on a threshold value has not been validated (4). In this study, an attempt was made to analyse mRNA levels of 3 genes (TS, TP, DPD) in colon tumors and bioclinical parameters in such a way as to predict clinical outcomes such as objective response rate (ORR), progression free survival (PFS) and OS based on these values. Furthermore, the ethical possibility of tailoring chemotherapy was investigated, so that in the future, 5-FU would not be proposed for patients likely to be non- responders (6). A retrospective study was performed on a population of 40 metastatic colon cancer patients diagnosed with at least one measurable metastatic site and with a precise clinical follow-up. After surgical removal of the primary tumor site, relative mRNA levels were determined by quantitative RT-PCR in a tumor sample. Thereafter, a statistical model was defined to describe the relationship between gene expression and response to chemotherapy.

To try and determine the value of chemotherapy and its subsequent effect on laryngeal preservation in patients presenting with laryngeal and pharyngeal carcinomas. One group was initially treated with surgery and radiotherapy. The second group was treated with chemotherapy and subsequent salvage surgery and/or radiotherapy. Their survival rates and laryngeal preservation rates were compared.From 251 patients the authors have retrospectively studied 124 patients with induction chemotherapy. The survival rate has been compared with a control group of 127 patients who was treated by initial surgery and radiotherapy.The survival rate at 5 years for the patients initially treated by surgery and radiotherapy was 64.1%. The survival for patients with a total clinical response following chemotherapy was 49.8% at 5 years. Survival with no total clinical response following chemotherapy treated by secondary radiotherapy was 25.7% at 3 years. The initial rate of laryngeal preservation is 32.2% but this rate fell to 22% after local recurrencies.The group with total clinical response after induction chemotherapy with laryngeal preservation have a non significantly difference in their survival compared with the group initially treated by surgery and radiotherapy. In contrary patients with non complete clinical response have a survival of 25.7% at 3 years. The rate of local recurrency of patients with laryngeal preservation is 32.5% and gives a finally rate of laryngeal preservation of 21%. These recurrencies decrease the survival rate.

Abstract Background: Olaparib is a PARP inhibitor that has shown high response rates and clinical activity in patients with advanced HER2-negative breast cancer (BC) and a germline BRCA1 and BRCA2 mutation. There is also evidence of cellular sensitivity to PARP inhibitors associated to defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI). Moreover, about 15% of patients with ER+/HER2- metastatic BC have at least 100 mutations in their tumor, leading to genomic instability and potential sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested the benefit of an association of immune checkpoint blockade, like durvalumab, with PARP inhibitor. Indeed, tumors with BRCA1/2 mutations or other deficiency in HRR have high mutagenic burden and produce a larger number of neoantigens. Most BRCA-associated BC are ER+/HER2-. Although loss of the BRCA gene function is a key driver of oncogenesis in these patients, ER-pathway appears to remain a key target for their therapy. Preclinical data indicate that olaparib may enhance endocrine therapy efficacy and circumvent resistance. Therefore, the combination of durvalumab, olaparib and endocrine therapy could be a therapeutic option for patients with BRCA1/2 mutation or for patients with selected ER+/HER2- advanced BC. Trial design: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab. Olaparib will be administered orally twice daily at 300 mg. Fulvestrant will be administered as two intramuscular injections of 250 mg (Cycle 1 Days 1 and 15, and Day 1 of each subsequent 28-day cycle). Durvalumab will be started 4 weeks after the first dose of olaparib at 1500 mg intravenous every 4 weeks. Eligibility criteria include: ER+/HER2- metastatic or locally advanced BC with documented germline alteration in BRCA1 or BRCA2 or deleterious germline or somatic alterations implicated in the HRR pathway (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes (AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor next generation DNA sequencing. Patients could have received 1 line of endocrine therapy and/or 1 line of chemotherapy in the metastatic setting.Specific aims: To evaluate the efficacy of the combination in terms of progression-free survival rate at 24 weeks using RECIST v1.1. Secondary endpoints include: safety (according to the NCI-CTCAE v5.0), overall survival, progression-free survival, objective response rate, duration of response in the overall study population and in the germline BRCA mutated population. Statistical methods: Given the lack of safety data from this association, a safety run-in of 6 patients was planned. With an optimum two-stage Simon design,α = 2.5%, β = 5%, p0 (the probability of inefficiency maximum) = 50%, p1 (the probability of minimum efficiency) = 65%, it would be necessary to include 149 evaluable patients. The strategy could be considered sufficiently effective if there are at least 87 successes. According to the established design (including a rate of 5% of patients lost to follow-up or non-evaluable), it will be necessary to include 158 patients. We hypothesized that about 20% of screened patients will have a molecular alteration to allow enrollment. Thus, we need to screen 790 patients. The study is recruiting. The safety run-in is over. By July 1, 2020, 62 patients have been screened and 8 have been treated (NCT04053322). Contact information: DOLAF@unicancer.fr Citation Format: Severine Guiu, Judith Balmana, Lise Roca, Anthony Goncalves, Audrey Mailliez, Frederic Bigot, Thomas Bachelot, Florence Dalenc, Nadine Dohollou, Dominique Genet, Isabelle Desmoulins, Camille Chakiba, Suzette Delaloge, Geraldine Martineau, Veronique Haddad, Philippe Follana. Dolaf- an international multicenter phase 2 trial of durvalumab (medi4736) plus olaparib plus fulvestrant in metastatic or locally advanced er-positive, her2-negative breast cancer patients selected using criteria that predict sensitivity to olaparib (UCBG308) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-05.

This article presents a comparison of the mode of breast cancer detection in two time periods 10 years apart (1986-1989 and 1997-1999). The first period was before the introduction of a mammography screening program in 1995, and the second period began several years later. The records of all women with breast cancer during these two periods were reviewed. From 1986 to 1989, 372 women were diagnosed with breast cancer (group 1), and from 1997 to 1999, there were 341 cases of breast cancer recorded (group 2). Both groups of women had a median age of 60 years. There was a greater number of women in group 2 who reported a family history of breast cancer (26% compared with 17% for group 1; P =.011). Otherwise patient characteristics were similar for both groups. In the first time period, 80.2% of all breast cancers were discovered by the patient, 10.2% were found by an examining physician, and 4.8% were detected by screening mammography. In comparison, there was a significant change in the mode of detection during the second period. In group 2, 51.9% of breast cancers were discovered by self-examination, 13.7% by a physician, and 29.1% by screening mammography (P < 10-18). Compared with group 1, the women in group 2 had smaller tumors with fewer lesions larger than 2 cm (P =.019). Tumors were classified as pT1 in 38.3% of the women in group 1 and 46.6% in group 2 (P =.044), as pT2 in 50.5% of group 1 and 47.6% of group 2 (NS), and as pT3 in 11% of group 1 and 5.7% of group 2 (P =.014). The women in group 2 had more lymph nodes removed during surgery than did the women in group 2 (11.1 vs. 9.3; P <.001). However, they had fewer positive lymph nodes and a lower incidence of metastases than the women in group 2. Surgical treatment was more common in group 2 (92.7% vs. 86% in group 1), but it was more likely to be conservative surgery (50.9% vs. 41.% for group 1). In both groups, overall and disease-free survival were greatest for women whose tumors were detected by mammography. Overall survival was significantly greater for detection by mammography than by physician examination (P =.0015), and disease-free survival was significantly greater when mammography was compared with patient self-examination (P =.0064).