Publications by authors named "Giulia Baciarello"

24 Publications

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Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?

Cancer Treat Rev 2021 Apr 5;97:102204. Epub 2021 Apr 5.

Drug Development Unit, Sarah Cannon Research Institute, London, UK; UCL Cancer Institute, University College London, UK.

The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient's outcomes. In that regard, CUP patients' outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the "true" CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group. Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials. Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes.
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http://dx.doi.org/10.1016/j.ctrv.2021.102204DOI Listing
April 2021

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.

Cell Death Dis 2021 03 11;12(3):258. Epub 2021 Mar 11.

Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, 94800, Villejuif, France.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
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http://dx.doi.org/10.1038/s41419-021-03540-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948172PMC
March 2021

A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience.

Oncologist 2021 May 25;26(5):e769-e779. Epub 2021 Mar 25.

Clinical Cooperation Unit Molecular Haematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Background: CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly guided therapy versus platinum-based chemotherapy in patients newly diagnosed with "unfavorable" cancer of unknown primary (CUP).

Materials And Methods: Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential patients with CUP entering screening undergo a review involving reference histopathology and clinical work-up by a central eligibility review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded.

Results: As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (n = 89), failure to meet inclusion and exclusion criteria not directly related to CUP diagnosis (n = 89), and other reasons (n = 33). A total of 124 (35.8%) patients were excluded because unfavorable adeno- or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into three groups ineligible because of (a) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (b) evidence of a possible primary tumor; or (c) noncarcinoma histology.

Conclusion: Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Reconfirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms.

Implications For Practice: A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. This article reports the authors' experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision-making regarding diagnosing true CUP cases; this will have far-reaching implications in the design, execution, and interpretation of not only CUPISCO but also future clinical studies aiming to find much-needed treatment strategies.
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http://dx.doi.org/10.1002/onco.13744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100559PMC
May 2021

QualFatigue study: which factors influence the use of specific interventions for breast cancer survivors with fatigue? A cross-sectional exploratory study.

Support Care Cancer 2021 Feb 5. Epub 2021 Feb 5.

Inserm, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.

Purpose: International guidelines recommend specific interventions to reduce cancer-related fatigue (CRF). Evidence suggests underutilization of these interventions among breast cancer survivors. The QualFatigue study aimed to explore the potential factors influencing the use of specific interventions, for relief, in patients with CRF through qualitative analyses.

Methods: Patients with stage I-III breast cancer, and CRF ≥4 on a 10-point numerical scale were recruited within 6-24 months at the end of their primary treatment. Semi-structured interviews were performed. Emergent themes were identified using a stepped content analysis (QDA Miner software).

Results: Data saturation was achieved with 15 interviews. Four main themes emerged as potential sources of influence in the participants' use of specific interventions: (1) expectations regarding the management of CRF, (2) representations of the benefits provided by the interventions, (3) individual physical and psychological conditions, and (4) social and environmental situations. Six key levers came out transversally to optimize the use of specific interventions to relieve CRF: (1) listening and recognition of the individual difficulties and needs; (2) individual and global health assessments; (3) information and advice on how to manage CRF; (4) discussion groups focused on the management of CRF; (5) group activities; and (6) professional and personalized guidance.

Conclusion: This study calls for multi-level action to address many persistent barriers and exploit levers in the management of CRF.
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http://dx.doi.org/10.1007/s00520-021-06040-zDOI Listing
February 2021

Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer.

Ther Adv Med Oncol 2020 23;12:1758835920978134. Epub 2020 Dec 23.

Department of Cancer Medicine, University of Paris Saclay, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, 94805, France.

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.
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http://dx.doi.org/10.1177/1758835920978134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768840PMC
December 2020

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design.

Oncologist 2021 03 14;26(3):e394-e402. Epub 2020 Dec 14.

German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg, Germany.

Background: Carcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.

Materials And Methods: Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined.

Results: A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.

Conclusions: Thirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.
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http://dx.doi.org/10.1002/onco.13597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930409PMC
March 2021

A qualitative evaluation of the use of interventions to treat fatigue among cancer survivors: A healthcare provider's view.

Eur J Cancer Care (Engl) 2021 Mar 15;30(2):e13370. Epub 2020 Nov 15.

Institut Gustave Roussy, Université Paris-Saclay, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France.

Objective: Cancer-related fatigue (CRF) is among the most common and distressing side effects of cancer treatment. Different types of interventions, including physical activity (PA), psychosocial and mind-body interventions, have been shown to reduce CRF. We aimed to explore HCPs' practices and barriers to refer patients towards interventions to reduce CRF.

Methods: We performed a qualitative study using key informant interviews among a sample of 20 HCPs including medical, surgical and radiation oncologists, pain specialists, nurses, psychologists, psychiatrists and physiotherapists recruited from breast, prostate and colorectal cancer disease groups from a comprehensive cancer centre.

Results: Most interviewees reported not to address CRF spontaneously during consultations. When the topic of CRF was brought up by patients, all interviewees acknowledged to recommend PA, whereas few would recommend psychosocial or mind-body interventions. Barriers to recommend interventions to manage CRF included: lack of knowledge about CRF and its treatment, lack of time and complexity of the referral due to their accessibility and cost.

Conclusion: In a diverse sample of HCPs, most acknowledged not to address CRF proactively with their patients, but identified several actionable barriers. Specific training on screening and management of CRF and improving the referral network dedicated to interventions need to be implemented.
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http://dx.doi.org/10.1111/ecc.13370DOI Listing
March 2021

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

Oncologist 2020 10 18;25(10):e1509-e1515. Epub 2020 Sep 18.

Center Hospitalier de l'Université de Montréal, Montreal, Canada.

Background: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs).

Materials And Methods: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options.

Results: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences.

Conclusion: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Implications For Practice: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.
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http://dx.doi.org/10.1634/theoncologist.2020-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543332PMC
October 2020

Long-term Castration-related Outcomes in Patients With High-risk Localized Prostate Cancer Treated With Androgen Deprivation Therapy With or Without Docetaxel and Estramustine in the UNICANCER GETUG-12 Trial.

Clin Genitourin Cancer 2020 12 7;18(6):444-451. Epub 2020 Apr 7.

Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France. Electronic address:

Introduction: Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects.

Patients And Methods: Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected.

Results: Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms.

Conclusion: Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery.
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http://dx.doi.org/10.1016/j.clgc.2020.03.017DOI Listing
December 2020

Liver tests increase on abiraterone acetate in men with metastatic prostate cancer: Natural history, management and outcome.

Eur J Cancer 2020 04 6;129:117-122. Epub 2020 Mar 6.

Gustave Roussy, Université Paris-Saclay, Oncology Medicine Department, Villejuif, F-94805, France. Electronic address:

Background: Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described.

Patients And Method: We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France.

Results: Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose.

Conclusion: Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.
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http://dx.doi.org/10.1016/j.ejca.2020.01.017DOI Listing
April 2020

New rising entities in cancer of unknown primary: Is there a real therapeutic benefit?

Crit Rev Oncol Hematol 2020 Mar 23;147:102882. Epub 2020 Jan 23.

University of Ioannina, Ioannina, Greece.

Cancers of Unknown Primary Site (CUP) account for approximately 1-3 % of all malignant neoplasms. It represents a heterogeneous group of malignancies without a detectable primary and is characterized by aggressive clinical behavior. Patients with CUP are presumably categorized into prognostic subsets according to their clinical and pathological characteristics. The majority of these patients are chemoresistant and treated with empiric chemotherapy regimens which yield limited survival. Recent diagnostic advances have led to the identification of a higher percentage of culprit primaries among which colorectal, lung and renal tumors. The empiric CUP regimens may be suboptimal in these patients which explain in part their poor prognosis. In the absence of prospective randomized studies to prove the benefit of site-specific therapy in these subsets, we reviewed the literature to assess whether CUP with colorectal, lung and renal - profiles should be treated similarly to the correspondent primary tumors.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102882DOI Listing
March 2020

[Management of metastatic testicular germ cell tumors].

Bull Cancer 2019 Oct 26;106(10):896-902. Epub 2019 Aug 26.

Université Paris-Saclay, Gustave-Roussy, Department of Cancer Medicine, 114, rue Edouard-Vaillant, Villejuif, France.

Metastatic testicular germ cell tumors are rare entities with a high cure rate owing to their major chemosensitivity. Current guidelines should be strictly followed to ensure maximal cure rate. Germ cell tumor treatment requires multidisciplinary skills and is based on cisplatin-based chemotherapy. The current challenge for these patients with favorable prognosis is to limit over- or under-treatment. Centralization of care for patients with these rare cancers is a key point to achieve the best chance of cure.
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http://dx.doi.org/10.1016/j.bulcan.2019.05.004DOI Listing
October 2019

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.

Hôpital Civil, Strasbourg, France.

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

Fatigue and physical activity in cancer survivors: A cross-sectional population-based study.

Cancer Med 2019 05 12;8(5):2535-2544. Epub 2019 Mar 12.

Department of Medical Oncology, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.

Purpose: A substantial proportion of cancer survivors experience fatigue after diagnosis. Physical activity (PA) can impact fatigue after cancer. In this study, we evaluated the prevalence and association of fatigue and the practice of PA in a population with early cancer.

Methods: Using the national population-based French cross-sectional study Vie après le cancer 2, we included 1984 patients with early breast (61.1%), prostate (21.5%), and colorectal (17.4%) cancer. Severe fatigue at 2 years postdiagnosis was defined by a score ≥40 in the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ C30) fatigue subscale. PA was defined as (a) self-reported PA before diagnosis (active/inactive) and (b) change in PA since diagnosis (increased/maintained exposure vs decreased exposure/remaining inactive). Multivariate regression examined associations of severe fatigue with PA, adjusting for baseline clinical and treatment variables.

Results: Median age was 52 years. 51.5% of patients experienced severe fatigue 2 years post-diagnosis. 87.7% reported to be physically active before cancer diagnosis; 53.3% of patients either decreased PA or remained inactive at 2 years postdiagnosis. At 2 years postdiagnosis, severe fatigue was associated with a change in PA since diagnosis: patients with decreasing PA/remaining inactive from pre- to postdiagnosis had a higher risk of severe fatigue vs those with increasing/maintaining PA (adjusted odds ratio [95% confidence interval] 2.32 [1.85-2.90]).

Conclusion: Fatigue continues to be a substantial problem for cancer survivors 2 years after cancer diagnosis and is associated with PA decreasing/remaining inactive since diagnosis. Interventions to maintain or increase PA for cancer survivors should be tested to mitigate long-term fatigue after cancer.
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http://dx.doi.org/10.1002/cam4.2060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536944PMC
May 2019

A Case of Heavily Pretreated Metastatic Germ Cell Tumor With Ongoing Long-term Complete Response After Gemcitabine Treatment.

Clin Genitourin Cancer 2019 06 26;17(3):e485-e487. Epub 2019 Jan 26.

Department of Cancer Medicine, Gustave Roussy, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2019.01.010DOI Listing
June 2019

Advancing therapies in metastatic castration-resistant prostate cancer.

Expert Opin Pharmacother 2018 11 12;19(16):1797-1804. Epub 2018 Oct 12.

a Department of Medical Oncology , Institut Gustave Roussy, University of Paris Sud , Villejuif , France.

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T.

Areas Covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies.

Expert Opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.
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http://dx.doi.org/10.1080/14656566.2018.1527312DOI Listing
November 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

Treatment of Castration-naive Metastatic Prostate Cancer.

Eur Urol Focus 2017 12 27;3(6):518-521. Epub 2018 Feb 27.

Institut Gustave Roussy, Département de Médecine Oncologique, Université Paris-Saclay, Villejuif, France. Electronic address:

Both docetaxel+androgen deprivation therapy (ADT) and abiraterone acetate 1000mg/d+prednisone/prednisolone 5mg/d+ADT improved survival in patients with metastatic castration-naive prostate cancer. Their use should be offered and guided by patient's own characteristics.
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http://dx.doi.org/10.1016/j.euf.2018.02.004DOI Listing
December 2017

Long-term complete remission with Ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients.

J Immunother Cancer 2017 18;5:31. Epub 2017 Apr 18.

Institut Gustave Roussy, University of Paris-Sud, Department of Cancer Medicine, 114 Rue Edouard Vaillant, 94800 Villejuif, France.

Background: Prostate cancer is one of the most common cancers in men and the fourth leading cause of cancer mortality worldwide. Although major progress has been achieved in the last years for patients with metastatic castrate-resistant prostate cancer (mCRPC), thanks to next-generation androgen receptor axis targeted drugs, taxanes, and bone-targeted agents, immunotherapy has not been widely approved and used for the treatment of prostate cancer. Two large studies with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody reported improved progression-free survival, but not statistically improved overall survival at the primary analysis (CA184 043 and CA184 095).

Case Presentation: Here, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months respectively after the initiation of ipilimumab. Immunohistochemical staining for hMLH1, hMSH2, hMSH6 and PMS2 was performed on archival prostate biopsy samples from one of the two patients; they exhibited normal protein expression. Interestingly for this patient, a high CD3+ and CD8+ T cell infiltration was observed on archival prostate biopsies as well as Treg FoxP3+ T cells.

Conclusion: Ipilimumab produces clinical activity in patients with CRPC, including very long responders with no detectable residual disease.
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http://dx.doi.org/10.1186/s40425-017-0232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394619PMC
June 2018

Predicting and preventing thromboembolic events in patients receiving cisplatin-based chemotherapy for germ cell tumours.

Eur J Cancer 2016 12 4;69:151-157. Epub 2016 Nov 4.

Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Sud, 94800 Villejuif, France. Electronic address:

Background: Patients with germ cell tumours (GCT) receiving cisplatin-based chemotherapy are at high risk of thromboembolic events (TEE). Previously, we identified serum lactate dehydrogenase (LDH) and body surface area (BSA) as independent predictive factors for TEE. The aim of this study was to validate these predictive factors and to assess the impact of thromboembolism prophylaxis in patients at risk of deep venous thrombosis (DVT).

Methods: Between 2001 and 2014, 295 patients received first-line cisplatin-based chemotherapy for GCT. Preventive anticoagulation with low-molecular-weight heparin (LMWH) was progressively implemented in patients with predictive factors. Sixteen patients with evidence of TEE before starting chemotherapy were excluded from the analysis.

Results: Among 279 eligible patients, a TEE occurred in 38 (14%) consisting of DVT (n = 26), arterial thrombosis (n = 2), and superficial thrombophlebitis (n = 10). DVT occurred in 26 (12.7%) of 204 patients with risk factors versus two (2.6%) of 75 patients with no risk factors (p = 0.01). After a prevention protocol was progressively implemented from 2005, primary thromboprophylaxis was administered to 104 patients (68%) with risk factors. Among patients at risk (n = 151), the incidence of DVT decreased by roughly half when they received a LMWH: 9/97 (9.2%) and 9/54 (16.6%), respectively (p = 0.23).

Conclusion: Patients with GCT who receive cisplatin-based chemotherapy are at risk of developing a TEE which can be predicted by elevated serum LDH. To our knowledge this is the first study exploring LMWH as thromboprophylaxis in GCT patients. A prospective trial testing prophylactic anticoagulation is warranted.
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http://dx.doi.org/10.1016/j.ejca.2016.10.003DOI Listing
December 2016

Treatment of metastatic castration-resistant prostate cancer (mCRPC) with enzalutamide.

Crit Rev Oncol Hematol 2016 Oct 15;106:14-24. Epub 2016 Jul 15.

Department of Medical Oncology, San Camillo and Forlanini Hospitals, Padiglione Flajani, Circonvallazione Gianicolense 87, Rome, 00152, Italy. Electronic address:

Prostate cancer is initially responsive to androgen deprivation therapy, but most patients eventually develop castration-resistant disease. Enzalutamide is an androgen receptor (AR) inhibitor that targets several steps in the AR signaling pathway and has shown significant efficacy in the treatment of metastatic castration-resistant prostate cancer in patients with or without prior chemotherapy. To provide optimal treatment, it is important to understand the implications of enzalutamide use in the context of other therapies, as recent findings have suggested cross-resistance occurs between and within drug classes. Mutations and splice variants of AR also impact the course of prostate cancer. Future strategies involving enzalutamide should account for previous exposure to taxanes or antiandrogen therapies and the presence of AR variants that could affect efficacy.
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http://dx.doi.org/10.1016/j.critrevonc.2016.07.005DOI Listing
October 2016

Early PSA response is an independent prognostic factor in patients with metastatic castration-resistant prostate cancer treated with next-generation androgen pathway inhibitors.

Eur J Cancer 2016 07 3;61:44-51. Epub 2016 May 3.

Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, Villejuif, France. Electronic address:

Background: The optimal use of new therapies in metastatic castration-resistant prostate cancer (mCRPC) remains to be clarified. Prostate-specific antigen (PSA) response used as a pharmacodynamic end-point may help identify patients with early resistance to new androgen receptor-pathway inhibitors. We aimed to determine the clinical significance of early PSA response (EPR) during therapy with enzalutamide, abiraterone acetate (AA) and orteronel in mCRPC.

Methods: Data from patients recruited in clinical trials were studied. PSA values were obtained at baseline and 28 d after treatment initiation. EPR defined as a decline >50% from baseline was calculated according to the Prostate Cancer Working Group 2 criteria. The effects of clinical characteristics on radiographic progression-free survival (rPFS) and overall survival (OS) were examined using the Cox model.

Results: EPR was assessed in 118 patients treated in clinical trials and was found to be associated with longer rPFS and OS (P < 0.0001 for both). Median rPFS was 13.9 and 5.6 months (hazard ratio [HR]:0.38, P < 0.001) for patients with and without an EPR, respectively. Median OS was 32.2 months in patients with an EPR and 15.9 months in patients without an EPR (HR: 0.4, P < 0.01). EPR remained prognostic for OS in multivariate analyses (HR: 0.5, p=0.009) that included validated pre-therapeutic prognostic factors for mCRPC. Prognostic values of EPR for rPFS and OS were confirmed in an independent cohort of 95 AA-treated non-trial patients.

Conclusions: EPR is an independent prognostic factor in patients with mCRPC treated with next-generation androgen pathway inhibitors and may be useful for the therapeutic management of these patients.
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http://dx.doi.org/10.1016/j.ejca.2016.03.070DOI Listing
July 2016

Randomized controlled trial of remote endarterectomy versus endovascular intervention for TransAtlantic Inter-Society Consensus II D femoropopliteal lesions.

J Vasc Surg 2012 Dec 6;56(6):1598-605. Epub 2012 Oct 6.

Department of Vascular and Endovascular Surgery, Policlinico Casilino, Rome, Italy.

Objective: This study evaluated outcomes of remote endarterectomy (RE) vs endovascular (ENDO) interventions on TransAtlantic Inter-Societal Consensus (TASC)-II D femoropopliteal lesions and identified factors predictive of restenosis.

Methods: From October 2004 to December 2008, 95 patients with TASC-II D lesions were randomized 1:1 to receive RE of the superficial femoral artery (SFA) with end point stenting (51 patients) or ENDO, consisting of subintimal angioplasty with stenting (44 patients). The groups were balanced for age, sex, atherosclerotic risk factors, and comorbidities. Categoric data were analyzed with χ2 tests, and time to event provided two-sided P values with a level of significance at .05 and 95% confidence intervals (CIs). Survival curves for primary patency were plotted using the Kaplan-Meier method. Univariate analysis for diabetes, hypertension, dyslipidemia, smoking, and critical ischemia was performed according to the Cox proportional hazards model.

Results: The mean follow-up was 52.5 months (range, 35-75 months). Five RE patients and four ENDO patients were lost to follow-up (censored). Primary patency was 76.5% (39 of 51) in RE and 56.8% (25 of 44) in ENDO (hazard ratio [HR], 2.6; 95% CI, 0.99-4.2; P=.05) at 24 months and was 62.7% (32 of 46) in RE and 47.7% (21 of 40) in ENDO (HR, 1.89; 95% CI, 0.94-3.78; P=.07) at 36 months. Assisted primary patency was 70.6% (36 of 51) in RE and 52.3% (23 of 44) in ENDO (HR, 2.45; 95% CI, 1.20-5.02; P=.01). Secondary patency overlapped the primary comparison data at 12 and 24 months; at 36 months, there was a slight but significative advantage for RE (HR, 2.26; 95% CI, 1.05-4.86; P=.03). Univariate analysis demonstrated that hypercholesterolemia and critical limb ischemia (CLI) were significantly related to patency failure, whereas diabetes was significant only in ENDO. These factors (hypercholesterolemia and CLI) were independent predictors of patency on Cox multivariate analysis.

Conclusions: RE is a safe, effective, and durable procedure for TASC-II D lesions. Our data demonstrate a significantly higher primary, assisted primary, and secondary patency of RE vs ENDO procedures. Furthermore, overall secondary patency rates remain within the standard limits, although preoperative CLI and dyslipidemia continue to be associated with worse outcomes. Taken together, these data suggest that RE should be considered better than an endovascular procedure in SFA long-segment occlusion treatment.
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http://dx.doi.org/10.1016/j.jvs.2012.06.081DOI Listing
December 2012