Publications by authors named "Aude Flechon"

91 Publications

Multicentric phase II trial of TI-CE high-dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors.

Cancer Med 2021 Mar 5. Epub 2021 Mar 5.

Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.

Background: High-dose chemotherapy (HDCT) with TI-CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug.

Methods: Patients with unfavorable relapsed GCT were treated according to TI-CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate.

Results: Eighty-nine patients who received HDCT were included in the modified intent-to-treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty-five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow-up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5-25.9) and OS was 46.3 m (95% CI: 18.6-not reached). For high- and very high-risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2-year PFS rate was 41.1%.

Conclusion: The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug.
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http://dx.doi.org/10.1002/cam4.3687DOI Listing
March 2021

Real-world evidence of cabozantinib in patients with metastatic renal cell carcinoma: Results from the CABOREAL Early Access Program.

Eur J Cancer 2021 Jan 27;142:102-111. Epub 2020 Nov 27.

Centre Hospitalier Universitaire Saint-André, Bordeaux, France.

Background: Real-world data on cabozantinib in metastatic renal cell carcinoma (mRCC) is limited. This study (CABOREAL) reports treatment patterns and outcomes for patients treated with cabozantinib through the French Early Access Program.

Patients And Methods: This multicentre (n = 26), observational, retrospective study enrolled patients with mRCC who had received ≥1 dose of cabozantinib. Overall survival (OS) was estimated using the Kaplan-Meier method; subgroups were compared using the log-rank test. A multiple Cox regression model assessed predictive factors of OS after cabozantinib initiation.

Results: Four hundred and ten recruited patients started treatment between September 2016 and February 2018: the Eastern Cooperative Oncology Group Performance Status ≥2, 39.3%; poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 31.7%; 0-1, 2 and ≥3 previous treatment lines, 25.3%, 33.4% and 41.2%, respectively; bone metastases, 55.9%; brain metastases, 16.8%. Median (min-max) follow-up was 14.4 (0-30) months. Overall, 57.0% of patients had a dose reduction, 15.6% an alternative dose schedule. The median average daily dose was 40.0 mg. Median (quartile [Q]1-Q3) treatment duration was 7.6 (0.1-29.1) months, median OS was 14.4 months, and the 12-month OS rate was 56.5% (95% confidence interval: 51.5-61.2). Most patients (54.4%) received subsequent treatment. Predictive factors associated with longer OS were body mass index ≥25 kg/m (p = 0.0021), prior nephrectomy (p = 0.0109), favourable or intermediate IMDC risk (p < 0.0001) and cabozantinib initiation at 60 mg/day (p = 0.0486).

Conclusions: In the largest real-world study to date, cabozantinib was effective in unselected, heavily pretreated patients with mRCC. Initiation at 60 mg/day was associated with improved outcomes. CLINICALTRIALS.

Gov Identifier: NCT03744585.
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http://dx.doi.org/10.1016/j.ejca.2020.09.030DOI Listing
January 2021

A Risk-benefit Analysis of Prophylactic Anticoagulation for Patients with Metastatic Germ Cell Tumours Undergoing First-line Chemotherapy.

Eur Urol Focus 2020 Oct 6. Epub 2020 Oct 6.

Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).

Objective: To assess the risk and onset of VTEs stratified by risk factors.

Design, Setting, And Participants: This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.

Intervention: Patients with prophylactic anticoagulation were excluded.

Outcome Measurements And Statistical Analysis: A regression analysis was performed to select risk factors for VTEs. The simulated number needed to treat (NNT) and the number needed to harm (NNH) with prophylactic anticoagulation were calculated based on the cumulative incidences retrieved from this study and hazard rates of recently published trials describing the efficacy of prophylactic anticoagulation to prevent VTEs and the risk of bleeding events.

Results And Limitations: From 1120 patients, 121 (11%) had a VTE, which occurred prior to chemotherapy in 49 (4%) and on or after chemotherapy in 72 (6%). Six patients (<1%) had a bleeding event without anticoagulation. After backward regression, the one risk factor for a VTE during or after chemotherapy was the use of a venous access device. The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy would translate into an NNT of 45 (95% confidence interval [CI] 36-56) and an NNH of 186 (95% CI 87-506). Limitations are mainly related to the retrospective nature of the study.

Conclusions: The mGCTs associated VTEs are most common before and during, but not after, chemotherapy. Avoiding venous access device and/or prophylactic anticoagulation with an acceptable risk-benefit profile may decrease VTE occurring on chemotherapy.

Patient Summary: We found that venous thromboembolic events (VTEs) occur rarely after chemotherapy. Based on experience of prophylactic anticoagulation in other cancers, we conclude that the risk of VTE in men undergoing chemotherapy for metastatic germ cell tumours can be decreased by thromboprophylaxis with a reasonable risk-benefit profile and by avoidance of venous access devices.
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http://dx.doi.org/10.1016/j.euf.2020.09.017DOI Listing
October 2020

Could Aberrant Migration Explain Metachronous Germ Cell Tumors?

Cancer Invest 2021 Feb 6;39(2):195-201. Epub 2020 Nov 6.

Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France.

Background: Extragonadal germ cell tumors (GCTs) are thought to arise as a result of local transformation of primordial gonadal cells (PGCs) that become misplaced during embryogenesis. With the exception of bilateral testis tumors, metachronous GCT (i.e., occurring at a site classically described for primary GCTs) are rare events.

Patients And Methods: The clinical, radiological, and molecular data (if available) of patients with metachronous GCT were analyzed.

Results: Three Caucasian males were identified: case 1 presented with a pineal germinoma 19 years after a mediastinal seminoma that had been treated with chemotherapy, case 2 presented with a pineal non-seminomatous GCT (NSGCT) that occurred three years after a mediastinal seminoma treated with chemotherapy, and case 3 presented with a mediastinal seminoma concomitant with a suprasellar germinoma that occurred two years after a stage I testicular NSGCT treated exclusively with surgery. None of these patients had a positive family history or disorder of sex development. Molecular data were available for cases 2 and 3. In case 2, a gene biallelic inactivation in the second tumor suggested chemoresistance to cisplatin. This was further confirmed by tumor progression during second-line treatment. In case 3, the molecular analysis revealed different profiles in the three tumors, thus suggesting distinct tumor cell origins.

Conclusion: These rare cases should alert clinicians of the possibility of multiple GCTs that should not be considered to be relapses. The underlying physiopathology is unknown, but multiple PGC mismigrations is a likely cause. Initial treatment with cisplatin may select chemo-resistant clones, thereby making the subsequent treatment more of a challenge.
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http://dx.doi.org/10.1080/07357907.2020.1828447DOI Listing
February 2021

Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial.

Cancer Cell 2020 10 10;38(4):489-499.e3. Epub 2020 Sep 10.

Department of Cancer Medicine, Gustave Roussy, University of Paris Saclay, 94800 Villejuif, France.

Metastatic castration-resistant prostate cancer (mCRPC) is immunologically "cold" and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3-4 treatment-related adverse events have occurred in ∼42%-53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented.
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http://dx.doi.org/10.1016/j.ccell.2020.08.007DOI Listing
October 2020

Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Secondary Endpoints: Chemotherapy Toxicity and Pathological Responses.

Eur Urol 2021 Feb 28;79(2):214-221. Epub 2020 Aug 28.

Department of Medical Oncology, Saint-Louis-APHP, Faculté de Paris, France.

Background: Perioperative chemotherapy (neoadjuvant or adjuvant) has been developed to increase overall survival for nonmetastatic muscle-invasive bladder cancer (MIBC). Retrospective studies or prospective phase II trials have been reported to use dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). As dd-MVAC has shown higher response rates in metastatic disease, better efficacy is expected in the perioperative setting.

Objective: We designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting.

Design, Setting And Participants: A total of 500 patients were randomized from February 2013 to March 2018 in 28 centers and received either six cycles of dd-MVAC every 2 wk or four cycles of GC every 3 wk.

Outcome Measurements And Statistical Analysis: The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses.

Results And Limitations: In the neoadjuvant group, 218 patients received dd-MVAC and 219 received GC. Of the patients, 60% received six cycles in the dd-MVAC arm and 84% received four cycles in the GC arm; 199 (91%) and 198 (90%) patients underwent surgery, respectively. Complete pathological response (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients, respectively (p=0.2). An organ-confined status (
Conclusions: The toxicity of dd-MVAC was manageable with more severe asthenia and GI side effects than that of GC in perioperative chemotherapy. A higher local control rate (complete pathological response, tumor downstaging, or organ confined) was observed in the dd-MVAC arm (p=0.021). However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.

Patient Summary: The authors have designed a randomized phase III controlled study comparing the efficacy of gemcitabine and cisplatin, and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) in patients for whom chemotherapy has been decided, before or after radical cystectomy. Higher toxicity regarding asthenia and gastrointestinal side effects along with a better bladder control rate were observed in the dd-MVAC arm. However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.
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http://dx.doi.org/10.1016/j.eururo.2020.08.024DOI Listing
February 2021

Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors.

Pharm Res 2020 Jul 16;37(7):147. Epub 2020 Jul 16.

Institut Claudius-Regaud, IUCT-Oncopole, Toulouse, France.

Background: Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol.

Methods: Eighty-eight patients received 400 mg/m/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.

Results: The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.

Conclusions: The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.
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http://dx.doi.org/10.1007/s11095-020-02861-5DOI Listing
July 2020

[Treatment of testicular germ cell tumors relapse].

Bull Cancer 2020 Sep 8;107(9):912-924. Epub 2020 Jul 8.

Département d'oncologie médicale, centre Léon-Bérard, 28, rue Laennec, 69337 Lyon cedex 08, France.

Seminomatous (SGCT) and non-seminomatous (NSGCT) germ cell tumors (GCT) are rare but their incidence are increasing. We will discuss different therapeutic strategies in relapse disease: patients with stage I germ cell tumor have an excellent prognosis with a cure rate approaching 98-99 %, whatever the histology and the chosen treatment (surveillance strategy or adjuvant treatment). Relapses are observed among 20% of patients with stage I SGCT or low risk NSGCT and 50 % of patients with high risk NSGCT. Patients are treated according to the international prognosis group (IGCCCG) for SGCT and low risk NSGCT, naïve of chemotherapy. After an adjuvant treatment, the protocol must be adapted to the number of previous cycles (1 or 2 BEP) and to the prognosis group. Five to 50% of patients relapse after a first line of metastatic chemotherapy according to initial prognosis group. Dose-dense chemotherapy according to the GETUG13 protocol reduces the risk of relapse for the patients with poor-risk group NSGCT and unfavorable tumor marker decline. The prognosis of patients with relapsed or refractory GCT after a first line is more negative since only half of them will be cured by salvage standard chemotherapy. An international therapeutic trial (TIGER) is ongoing in first line salvage treatment evaluating high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT). Finally, developing biomarkers for predicting clinical relapse, the management in expert centers of these patients and participation in therapeutic innovation are important perspectives for a better understanding and treatment of these patients with a poorer prognosis.
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http://dx.doi.org/10.1016/j.bulcan.2020.03.012DOI Listing
September 2020

[Intensification by high dose chemotherapy for germ-cell tumors, still an ongoing subject?]

Bull Cancer 2020 Jun;107(5S):S41-S48

Département de cancérologie médicale, centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France.

More than 80 % of patient with metastatic germ cell tumor are cured with first line chemotherapy. Twenty to 30 % of patients will experience relapse or refractory disease with a very poor long-term prognosis. Most of them had metastatic germ cell tumors with a poor prognosis according to the international germ cell classification collaborative group (IGCCCG). The role of treatment intensification by high dose chemotherapy (HDCT) followed by stem cell rescue has not been demonstrated yet in the first line setting compared to standard chemotherapy. The role of HDCT in first or second salvage is also not yet demonstrated, many studies have been published in this situation with a lot of different regimen. Outside clinical trial, HDCT remains an option in salvage therapy, depending on many factors including prognostics factors, previous therapy, general condition and reference center consideration to select eligible patient who could benefit the most of this approach. Results from the international randomized trial TIGER will provide evidence-based information for HDCT strategy.
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http://dx.doi.org/10.1016/S0007-4551(20)30277-0DOI Listing
June 2020

Brain metastases from germ cell tumor: time to reconsider radiotherapy?

Crit Rev Oncol Hematol 2020 Jun 16;150:102946. Epub 2020 Apr 16.

Department of Medical Oncology, Institut Claudius Regaud / Institut Universitaire du Cancer de Toulouse - Oncopole, 1 avenue Irène Joliot-Curie, 31000, Toulouse, France. Electronic address:

The presence of brain metastases (BMs) from germ cell tumor (GCT) remains a rare situation. BMs predominantly occur among patients with testis primary tumor site, and are almost exclusively associated with non-seminomatous (NS) histologies. Two situations must be distinguished, which differ in terms of clinical presentation, overall prognostic and management. At diagnosis, BMs are almost systematically associated with extra-cerebral metastases and the cornerstone of treatment is chemotherapy, while the role of local treatment remains controversial. In the metachronous setting, BMs more frequently constitute an isolated site of relapse, the outcome is poorer, and the role of local treatment is more consensual. However, all these data widely come from old reports, with outdated radiation techniques. The recent advances in radiation oncology, especially the rising use of stereotactic radiotherapy, could lead to the reconsideration of ancient dogmas regarding the "radiosensitivity" of (NS)GCT and the role of radiotherapy among patients with BMs.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102946DOI Listing
June 2020

Axitinib in first-line for patients with metastatic papillary renal cell carcinoma: Results of the multicentre, open-label, single-arm, phase II AXIPAP trial.

Eur J Cancer 2020 04 5;129:107-116. Epub 2020 Mar 5.

Medical Oncology, Gustave Roussy, Villejuif, France.

Introduction: Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC.

Methods: This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status ≤ 1 and adequate organ functions. PRCC had to be confirmed by histology expert central review. Axitinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review.

Results: Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1-39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to +∞), the objective response rate was 28.6% (95% CI, 15.7%-44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5-9.2), 6.7 months (95% CI, 5.5-9.2) and 6.2 months (95% CI, 5.4-9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8-not reached). Adverse events were as expected; grade 3-4 treatment-related adverse events were rare except hypertension (27%).

Conclusions: Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting.

Clinical Trial Registration: ClinicalTrials.gov, NCT02489695.
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http://dx.doi.org/10.1016/j.ejca.2020.02.001DOI Listing
April 2020

[Docetaxel for octogerian metastatic castration-resistant prostate cancer patient: A multicentric ten years' experience].

Bull Cancer 2020 Feb 31;107(2):171-180. Epub 2019 Dec 31.

Institut de cancérologie Lucien-Neuwirth, département d'oncologie médicale, 108, bis avenue Albert-Raimond, BP60008, 42271 Saint-Priest-en-Jarez cedex, France.

Introduction: There is very few data about the management of elderly patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to analyze the management of patients aged 80 and over treated with docetaxel for a mCRPC.

Methods And Materials: Clinical and pathological characteristics of octogerians treated with docetaxel were collected retrospectively from 3 French centers from 2009 to 2019. Patient's outcome, treatments administered before and/or after docetaxel were also analyzed.

Results: Data of 89 patients could be analyzed. A total of 20.2 % of patients received the standard regimen and 79.8 % received an adapted one. Patients in the adapted group were significantly older than in standard one. Other patient's characteristics - including the geriatric scales - were similar. Dose reductions for toxicity were more frequent in the standard group (P=0.04). The median overall survival of the total population was 13.3 months. It was longer in the standard group than in the adapted group (26.1 months vs 12.4 months=0.01). In multivariate analysis, the type of docetaxel regimen (standard versus adapted) was an independent predictor of survival.

Conclusion: This study suggests the benefit of the standard management even in oldest patients. A geriatric evaluation should certainly be processed in patients with poor oncogeriatric scale in order to select the sub-population able to receive the full dose standard docetaxel regimen.
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http://dx.doi.org/10.1016/j.bulcan.2019.11.006DOI Listing
February 2020

Neuroendocrine Carcinoma of the Urinary Bladder: A Large, Retrospective Study From the French Genito-Urinary Tumor Group.

Clin Genitourin Cancer 2020 08 5;18(4):295-303.e3. Epub 2019 Dec 5.

Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France; Association pour la Recherche et les Thérapeutiques Innovantes en Cancérologie, Paris, France; University René Descartes, Paris, France.

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.

Materials And Methods: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.

Results: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.

Conclusions: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.
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http://dx.doi.org/10.1016/j.clgc.2019.11.014DOI Listing
August 2020

Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database.

Eur J Cancer 2020 01 29;125:153-163. Epub 2019 Nov 29.

European Georges Pompidou Hospital, Paris, France. Electronic address:

Aim Of The Study: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry.

Methods: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence.

Results: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes.

Conclusions: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.
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http://dx.doi.org/10.1016/j.ejca.2019.10.030DOI Listing
January 2020

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.

Lancet Oncol 2020 01 18;21(1):105-120. Epub 2019 Nov 18.

Barts Cancer Institute, Queen Mary University of London, London, UK.

Background: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.

Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m (60 mg/m in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.

Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.

Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S1470-2045(19)30668-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880PMC
January 2020

Large retroperitoneal lymphadenopathy and increased risk of venous thromboembolism in patients receiving first-line chemotherapy for metastatic germ cell tumors: A study by the global germ cell cancer group (G3).

Cancer Med 2020 01 12;9(1):116-124. Epub 2019 Nov 12.

Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Background: Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life-threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population.

Methods: Data were collected from mGCT patients receiving first-line platinum-based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long-axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed.

Results: Data from 1135 patients were collected. Median age was 31 years (range 10-74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P < .001) and was associated with significantly higher risk of VTE in univariable analysis (22% vs 8%, OR 3.0, P < .001) and multivariable analysis (OR 1.8, P = .02). Other significant risk factors included, Khorana score ≥3 (OR 2.6, P = .008) and VAD use (OR 2.7, P < .001).

Conclusions: Large RPLN and VAD use are independent risk factors for VTE in mGCT patients receiving chemotherapy. VAD use should be minimized in this population and thromboprophylaxis might be considered for large RPLN.
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http://dx.doi.org/10.1002/cam4.2674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943085PMC
January 2020

Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database.

Eur Urol Oncol 2018 12 8;1(6):467-475. Epub 2018 Jun 8.

European Georges Pompidou Hospital, Paris, France. Electronic address:

Background: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown.

Objective: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences.

Design, Setting, And Participants: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016.

Outcome Measurements And Statistical Analysis: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity.

Results And Limitations: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3.

Conclusions: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs.

Patient Summary: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.
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http://dx.doi.org/10.1016/j.euo.2018.05.009DOI Listing
December 2018

[Securing patients pathways treated by oral antitumoral: Guidelines for better organization of departments and management of incoming calls].

Bull Cancer 2019 Jun 21;106(6):514-526. Epub 2019 May 21.

CHU Henri-Mondor, 51, avenue Mal-De-Lattre-De-Tassigny, 94000 Créteil, France; Centre François-Baclesse, 3, avenue du Général-Harris, 14076 Caen, France.

The emergence of oral cancer treatment in oncology has shifted patient follow-up from the hospital to the home. This trend has resulted in an increase in phone and e-mail interactions initiated by patients, but also by pharmacists, by liberal nurses, by general practitioners, and an increase in calls to the emergency response services (SAMU) both for real or perceived emergencies. This increased volume of patient and pharmacist communication has caused significant disruption in the daily activity of affected oncology departments and in particular of the secretariats. The procedures for formulating and securing appropriate responses within a short time frame are generally not established, and as a result, there is a risk that decisions made could be inappropriate for the patient's situation, especially in the case of complications.. Tracking responses to phone calls is necessary and answers should be noted in the medical file, including side effects, in particular the serious AEs for a good quality of care. This guideline describes best practices for oncologists who manage "incoming" calls from patients or professionals involved in the care pathway.
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http://dx.doi.org/10.1016/j.bulcan.2019.03.015DOI Listing
June 2019

Estimation of Unbound Carboplatin Clearance From Total Plasma Concentrations as a Means of Facilitating Therapeutic Drug Monitoring.

Ther Drug Monit 2019 02;41(1):66-74

Institut Claudius-Regaud, IUCT-Oncopole, Toulouse.

Background: Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations.

Methods: U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU.

Results: The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from -31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from -41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from -33% to +37%); MAPE = 11.4%].

Conclusions: The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.
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http://dx.doi.org/10.1097/FTD.0000000000000569DOI Listing
February 2019

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet Oncol 2018 07 4;19(7):975-986. Epub 2018 Jun 4.

Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.

Background: Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status.

Methods: We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients.

Findings: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8-20·4) with olaparib and abiraterone and 8·2 months (5·5-9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44-0·97, p=0·034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group.

Interpretation: Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(18)30365-6DOI Listing
July 2018

Efficacy of cabazitaxel rechallenge in heavily treated patients with metastatic castration-resistant prostate cancer.

Eur J Cancer 2018 07 7;97:41-48. Epub 2018 Apr 7.

European Georges Pompidou Hospital, Paris, France; René Descartes University, Paris V, France. Electronic address:

Background: Treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (DOC), cabazitaxel (CABA) and new hormone therapy (NHT) is limited. Rechallenge with DOC is limited because of cumulative toxicities. This study investigated the activity and safety of CABA rechallenge in mCRPC.

Patients And Methods: Clinical data were collected retrospectively in 17 centres in Europe. Eligible patients had undergone rechallenge with cabazitaxel after three previous lines of treatment (DOC, NHT and CABA, in any order). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Data on toxicities were collected.

Results: A total of 69 of 562 patients (Eastern Cooperative Oncology Group performance status 0-1 69%) were rechallenged with CABA (25 mg/m q3w, 58%; 20 mg/m q3w, 27.5%; other, 14.5%) for 1-10 (median 6) cycles; 76.8% received prophylactic granulocyte colony-stimulating factor. Median radiological or clinical PFS with CABA rechallenge was 7.8 months and 11.9 months with initial CABA therapy. OS was 13.7 months (95% confidence interval [CI]: 9.3-15.7) from the first CABA rechallenge cycle, 59.9 months (47.8-67.1) from the first life-extending therapy in mCRPC and 78.3 months (66.4-90.7) from mCRPC diagnosis. Best clinical benefit was improved (34.3%) or stable (47.8%). Lack of response to rechallenge occurred in 17.9% of patients (3.1% with initial CABA). The level of prostate-specific antigen decreased by ≥ 50% in 24% of patients at rechallenge (71% with initial CABA). There was no grade ≥III peripheral neuropathy or nail disorders.

Conclusions: CABA rechallenge may be a treatment option without cumulative toxicity in heavily pretreated patients with mCRPC who are still fit and had a progression >3 months after the last CABA injections.
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http://dx.doi.org/10.1016/j.ejca.2018.03.008DOI Listing
July 2018

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor-Targeted Agents.

Clin Genitourin Cancer 2018 08 23;16(4):e777-e784. Epub 2018 Feb 23.

Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France. Electronic address:

Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).

Patients And Methods: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined.

Results: A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA.

Conclusion: OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.
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http://dx.doi.org/10.1016/j.clgc.2018.02.016DOI Listing
August 2018

Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.

Lancet 2018 02 18;391(10122):748-757. Epub 2017 Dec 18.

Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France.

Background: Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population.

Methods: We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m, paclitaxel 175 mg/m, or 75 mg/m docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807.

Findings: Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6-15·5; n=116] vs 10·6 months [8·4-12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63-1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6-13·2]; HR 0·57, 95% CI 0·26-1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).

Interpretation: Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.

Funding: F Hoffmann-La Roche, Genentech.
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http://dx.doi.org/10.1016/S0140-6736(17)33297-XDOI Listing
February 2018

Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial.

Lancet Oncol 2017 11 9;18(11):1532-1542. Epub 2017 Oct 9.

Gustave Roussy, University of Paris Saclay, Villejuif, France.

Background: Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with metastatic castration-resistant prostate cancer. Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that inhibits the production of clusterin, an antiapoptotic protein that is upregulated in response to chemotherapy and that confers treatment resistance. We aimed to assess whether custirsen in combination with cabazitaxel and prednisone increases overall survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.

Methods: In this randomised, open-label, international, phase 3 trial, men with radiographically documented metastatic castration-resistant prostate cancer that had progressed after docetaxel treatment with a Karnofsky performance status of more than 70% and who were fit for chemotherapy, were recruited from 95 cancer treatment centres in eight countries. Patients were randomly assigned (1:1) centrally using permuted blocks (block size 8) to receive cabazitaxel plus prednisone (cabazitaxel 25 mg/m intravenously every 21 days plus oral prednisone 10 mg daily) with or without custirsen (640 mg intravenously on days 1, 8, and 15, plus three previous loading doses) until disease progression, unacceptable toxicity, or the completion of ten treatment cycles. Randomisation was stratified by use of opioids for prostate cancer-related pain at screening, disease progression following first-line docetaxel treatment established by radiographic evidence, and previous treatment with abiraterone or enzalutamide. The co-primary endpoints were overall survival in all randomly assigned patients and in a poor-prognosis subgroup. All analyses were intention to treat with the exception of safety, which was reported for patients who received any assigned treatment. The trial has been completed and the results presented here are the final analysis. This trial is registered with Clinicaltrials.gov, number NCT01578655.

Findings: Between Sept 9, 2012, and Sept 29, 2014, 795 patients were screened for enrolment. 635 men were eligible for inclusion and were randomly assigned (n=317 in the cabazitaxel and prednisone plus custirsen group and n=318 in the cabazitaxel and prednisone group). Median follow up was 28·3 months (IQR 24·4-34·5) for the custirsen group and 29·8 months (IQR 25·3-35·2) for the control group. Median overall survival in all randomly assigned patients did not differ between the two groups (14·1 months [95% CI 12·7-15·9] in the curtisen group vs 13·4 months [12·1-14·9] in the control group; hazard ratio [HR] 0·95 [95% CI 0·80-1·12]; log-rank p=0·53). In the poor prognosis subgroup, median overall survival also did not differ between the two treatment groups (11·0 months [95% CI 9·3-13·3] in the custursin group vs 10·9 months [8·2-12·4] in the control group; HR 0·97 [95% CI 0·80-1·21]; two-sided p=0·80). The most frequently reported grade 3 or worse adverse events in the custirsen versus control groups were neutropenia (70 [22%] of 315 vs 61 [20%] of 312), anaemia (68 [22%] vs 49 [16%]), fatigue (23 [7%] vs 18 [6%]), asthenia (16 [5%] vs 8 [3%]), bone pain (16 [5%] vs 5 [2%]), and febrile neutropenia (16 [5%] vs 9 [3%]). Serious adverse events were reported in 155 (49%) versus 132 (42%). 27 patients died within 30 days of treatment in the cabazitaxel and prednisone plus custirsen group, seven of which were deemed to be treatment related, versus 17 in the cabazitaxel and prednisone group, eight of which were deemed to be treatment related. Of the 21 deaths reported, 15 were reported as complications related to study treatment, either chemotherapy (eight and three, respectively) or study drug (none and four, respectively).

Interpretation: We noted no survival benefit in men with metastatic castration-resistant prostate cancer with the addition of custirsen to cabazitaxel and prednisone treatment. Cabazitaxel and prednisone remains the standard of care for patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy.

Funding: OncoGenex Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(17)30605-8DOI Listing
November 2017

Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study.

Clin Cancer Res 2017 Dec 19;23(23):7171-7179. Epub 2017 Sep 19.

Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.

We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83) × (BW/76) × (Age/36) with Scr in μmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations. TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1344DOI Listing
December 2017

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial.

Lancet 2017 Nov 12;390(10109):2266-2277. Epub 2017 Sep 12.

Barts Cancer Institute, Queen Mary University of London, London, UK.

Background: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population.

Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125.

Findings: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab.

Interpretation: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S0140-6736(17)32365-6DOI Listing
November 2017

[French national survey on incoming phone calls in oncology departments].

Bull Cancer 2017 Jun 6;104(6):565-573. Epub 2017 Apr 6.

Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France.

Introduction: Oral therapies have shifted the follow-up of patients with cancer from hospital to home. As a consequence, the number of incoming calls has increased. To understand the source, reasons, management and burden of calls, we underwent a French national survey. The objective was to describe the way calls are managed in oncology departments.

Methods: The study was a prospective survey in a representative sample of French oncology specialists using oral therapies.

Results: Among 51 participating onco/radiotherapy departments, 86 % of specialists were oncologists or hematologists and 14 % radiation oncologists. Eighty percent were from public centers and 20 % from private ones. The median number of calls/week was 110. Sixty-six percent of calls were from patients and families and 23 % from general practitioners. Upon calls reception by the secretaries, half of them corresponded to a medical question. Sixty-five percent of centers did not have an established specific procedure and 70 % of responders did not specifically train their teams to address the management of calls. Sixty-five percent of the specialists spent more than 30min/day. Most of them considered it disturbing medical activities. Sixty-six percent of patients calls were related to adverse effects of treatments. Twenty-two percent of specialists declared at least one severe adverse effect linked to misinterpretation of a call.

Discussion: With the increase of oral therapies, incoming phone calls represent an important burden of work. To improve calls management, adaptations of organizations are needed.
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http://dx.doi.org/10.1016/j.bulcan.2017.02.008DOI Listing
June 2017

Adjuvant radiotherapy after radical cystectomy for muscle-invasive bladder cancer: A retrospective multicenter study.

PLoS One 2017 6;12(4):e0174978. Epub 2017 Apr 6.

Department of Radiotherapy, Institut Bergonié, Bordeaux,France.

Objectives: Radical cystectomy (RC) and pelvic lymph-node dissection (LND) is standard treatment for non-metastatic muscle-invasive urothelial bladder cancer (MIBC). However, loco-regional recurrence (LRR) is a common early event associated with poor prognosis. We evaluate 3-year LRR-free (LRRFS), metastasis-free (MFS) and overall survivals (OS) after adjuvant radiotherapy (RT) for pathological high-risk MIBC.

Material And Methods: We retrospectively reviewed data from patients in 3 institutions. Inclusion criteria were MIBC, histologically-proven urothelial carcinoma treated by RC and adjuvant RT. Patients with conservative surgery were excluded. Outcomes were evaluated by Kaplan-Meier method. Acute toxicities were recorded according to CTCAE V4.0 scale.

Results: Between 2000 and 2013, 57 patients [median age 66.3 years (45-84)] were included. Post-operative pathological staging was ≤pT2, pT3 and pT4 in 16%, 44%, and 39%, respectively. PLND revealed 28% pN0, 26% pN1 and 42% pN2. Median number of lymph-nodes retrieved was 10 (2-33). Forty-eight patients (84%) received platin-based chemotherapy. For RT, clinical target volume 1 (CTV 1) encompassed pelvic lymph nodes for all patients. CTV 1 also included cystectomy bed for 37 patients (65%). CTV 1 median dose was 45 Gy (4-50). A boost of 16 Gy (5-22), corresponding to CTV 2, was administered for 30 patients, depending on pathological features. One third of patients received intensity-modulated RT. With median follow-up of 40.4 months, 8 patients (14%) had LRR. Three-year LRRFS, MFS and OS were 45% (95%CI 30-60), 37% (95%CI 24-51) and 49% (95%CI 33-63), respectively. Five (9%) patients had acute grade ≥3 toxicities (gastro-intestinal, genito-urinary and biological parameters). One patient died with intestinal fistula in a septic context.

Conclusions: Because of poor prognosis, an effective post-operative standard of care is needed for pathological high-risk MIBC. Adjuvant RT is feasible and may have oncological benefits. Prospective trials evaluating this approach with current RT techniques should be undertaken.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383060PMC
September 2017