A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR).

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Association of chemotherapy and comorbidities with overall survival in elderly patients with early breast cancer: a French population-based propensity score-matched analysis.

BACKGROUND: Additional systemic treatment for early breast cancer in elderly is challenged by increasing comorbidities with age. We aimed to examine the effect of additional chemotherapy on overall survival in patients aged 70 years or older and the impact of comorbidities on chemotherapy benefit. METHODS: This retrospective monocentric cohort study includes data from all patients aged 70 years and older who underwent surgery for an early breast cancer from 1997 to 2016. A propensity score analysis allowed adjustment for chemotherapy prescription preferences based on tumour characteristics. RESULTS: Of 15,599 patients who had surgery for an early breast cancer, 1743 (11.2%) over 70 years old were included, of whom 269 (15.4%) had received additional chemotherapy. Median follow-up was 5.3 years. Multivariate analyses on the propensity-score weighted cohort (n = 1 354) identified improved overall survival in patients with chemotherapy versus without (HR 0.54, 95% CI 0.31-0.92). Chronic obstructive pulmonary disease (HR, 2.16, 95% CI 1.40-3.34) and polypharmacy (HR 1.40, 95%CI 1.07-1.84) were associated with worse overall survival. No statistically significant interactions were identified between these comorbidities and chemotherapy prescription. CONCLUSION: Additional chemotherapy in elderly with early breast cancer is feasible and associated with overall survival benefit, supporting the importance of chemotherapy considerations in this population, and of avoiding undertreatment based on chronological age considerations alone.

Determination of different social groups' level of knowledge about malaria in a multicultural Amazonian cross-border context.

BACKGROUND: A steady decline in the number of cases of malaria was observed in the 2000s in French Guiana. This enabled regional health policies to shift their public health goal from control to elimination. To include inhabitants in this strategy, the main objective of this study was to describe knowledge about malaria, and related attitudes and practices in persons living in the French Guiana border. METHODS: We conducted a survey in people over 15 years old living in the twelve neighbourhoods of Saint-Georges de l'Oyapock with the highest malaria incidence. It comprised a 147-item questionnaire which collected data on socio-demographic characteristics and included a Knowledge Attitude and Practices survey on malaria. Knowledge-related data were studied using exploratory statistical methods to derive summary variables. A binary variable assessing level of knowledge was proposed and then assessed using exploratory approaches. RESULTS: The mean age of the 844 participants was 37.2 years [15.8], the male/female sex ratio was 0.8. In terms of nationality, 485 (57.5%) participants were Brazilian and 352 (41.7%) French. One third (305, 36.1%) spoke Brazilian Portuguese as their native language, 295 (34.9%) the Amerindian language Palikur, 36 (4.3%) French. The symptoms of malaria and prevention means were poorly known by 213 (25.2%) and 378 (44.8%) respondents, respectively. A quarter (206, 24.4%) did not know that malaria can be fatal. Overall, 251 people (29.7%) had an overall poor level of knowledge about malaria. Being under 25 years old, living in a native Amerindian neighbourhood, having an Amerindian mother tongue language, having risk behaviours related to gold mining were significantly associated with a poor level of knowledge. CONCLUSIONS: This study is the first to describe the poor level of knowledge about malaria in populations living in the malaria endemic border area along the Oyapock river in French Guiana. Results will allow to reinforce, to diversify and to culturally adapt prevention messages and health promotion to increase their effectiveness with a view to quickly reaching the goal of malaria elimination through empowerment.

Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVES: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status. METHODS: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status. RESULTS: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates). CONCLUSIONS: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone.

Mortality of patients with solid and haematological cancers presenting with symptoms of COVID-19 with vs without detectable SARS-COV-2: a French nationwide prospective cohort study.

BACKGROUND: Over 30 million COVID-19 cases have been diagnosed worldwide from late 2019. Among frail persons, cancer patients are at high risk of death from COVID-19. METHODS: The French prospective cohort ONCOVID-19 enrolled patients with solid or haematological tumour, receiving anticancer treatment and presenting with clinical symptoms suggestive of COVID-19. COVID-19 was confirmed through detectable SARS-CoV2 by RT-PCR (repeated twice if negative first) and/or specific CT-scan. The study aims to assess the 28-day mortality rate after the first COVID test. RESULTS: From March 1st to May 21st 2020, 23 French cancer centres and hospitals enrolled 1230 cancer patients with suspicion of COVID-19, including 1162 (94.5%) matching the inclusion criteria. We identified 425 (36.6%) COVID-19 positive patients including 155 (13.3%) diagnosed with CT-scan only, while 737 (63.4%) patients were COVID-19 negative. Death at day-28 occurred in 116/425 (27.8%) COVID-19 positive patients, and in 118/737 (16.3%) COVID-19 negative patients (p < 0·0001). With a median follow-up of 2.1 (1.6-2.4) months, 310 (26.7%) deaths were reported including 143 (33.6%) in the COVID-19 positive population, and 167 (22.7%) in the COVID-19 negative patients. Male gender, age, metastatic disease, immunosuppressive treatments, lymphopenia, COVID-19 diagnosis and diabetes were independent risk factors for death. CONCLUSION: Patients with solid and haematological cancers presenting COVID-19 symptoms with SARS-CoV-2 RT-PCR confirmed or not are both at high-risk of early mortality. COVID-19 is reported as the cause of death in 50% of COVID-19 positive patients with cancer. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, number NCT04363632.

Renouncing care in French Guiana: the national health barometer survey.

BACKGROUND: In French Guiana, health inequalities are patent for a broad range of pathologies for all age groups. The objective of the present study was to quantify the proportion of the population that had renounced care in the past year, to study predictive factors, and to compare results with other French territories. METHODS: A two-stage random sample of 2015 individuals aged 15 to 75 years was surveyed by telephone. A descriptive analysis of variables relative to renouncing care, use of health care, screening, and vaccination was initially performed. Multivariate analysis was then used to determine variables associated with renouncing care for financial reasons and renouncing for reasons linked to time were directly estimated using a Poisson model on weighted data. Variables with a significance level < 0.2 in the bivariate analysis were included in the full multivariate model. RESULTS: In French Guiana, during the past 12 months, 30.9% of surveyed persons renounced care whatever the type for financial reasons. Results of the multivariate analysis showed that gender, perceived financial situation, perceived health and complementary insurance status were independent predictive factors of care renouncement for financial reasons. Overall, 24% of the surveyed population declared having renounced to care for time-related motives. The independent predictors for time-related renouncing were different than those for renouncing care for financial reasons: a higher education level and a poor perceived health were independently associated with time-related renouncement; retired persons and students were found to renounce care less frequently than persons with a job. CONCLUSIONS: Renouncing for financial reasons, a major target of the 2016 health law, represented a public health problem in French Guiana. Renouncing for lack of time was an important motive for renouncing, which is aggravated by the insufficient number of health professionals, but may benefit from organizational solutions. There are avenues for improvement of health for the most vulnerable: promote health, act on risk factors, and facilitate the readability and accessibility of the health system. Recent reforms to stabilize health insurance may however have some adverse consequences for migrants.

Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis. METHODS: In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial. FINDINGS: Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3-97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]). INTERPRETATION: More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted. FUNDING: Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.

A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients.

BACKGROUND: Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. METHODS: Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy. RESULTS: From January 2012 to June 2015, 20 pts. (median age 43 years [21-67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. CONCLUSIONS: Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. TRIAL REGISTRATION: The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Descriptive epidemiology of suicide attempts and suicide in the remote villages of French Guiana.

OBJECTIVE: The overall rate of suicide in French Guiana is estimated at 6 per 100,000, a rate that is lower than in mainland France. Given the frequent reports of suicide in Amerindian communities, our hypothesis was that this figure fails to capture a more contrasted reality. Our objective was to refine estimates and determine suicide rates in remote villages of French Guiana. METHODS: We included patients for whom a suicide attempt or suicide was mentioned in medical records. The Health centers were grouped into two zones according to geographical remoteness. RESULTS: The highest suicide rates observed in the remote Amerindian villages of Camopi and Trois Sauts were, respectively, 118 and 78/100,000. The median age at the time of suicide was significantly younger in remote zones [23 years (95% CI 21.59-25.06)] than in non-remote zones-[27 years (95% CI 24.47-29.31)]. The most frequent methods were hanging (78%) and intoxication (22%). CONCLUSIONS: The suicide rate in remote areas in French Guiana was eight times higher than in France. The suicide of young people in remote areas in French Guiana and specifically in Amerindian villages must be better understood and prevented with contextualized and adapted care.

Factors associated with sexual risk taking behavior by precarious urban migrants in French Guiana.

BACKGROUND: French Guiana is highly affected by HIV. The migrant population is particularly susceptible. The objective of this study was to evaluate the level of risk of HIV transmission and its perception among migrants in French Guiana and to identify predictive factors. METHODS: An HIV/AIDS Knowledge, Attitudes, Behaviors and Practices study was conducted in 2012 among migrants living in precarious neighborhoods of French Guiana. RESULTS: Of the 1039 participants surveyed, 893 were analyzed, of which 35.6% had risky sex during the past 12 months. Sexual risk taking was higher among the migrant population than in the general population. The predictors of sexual risk taking behavior were: younger age groups, males, having a job, not living with a spouse, having first had sex before age 16, using alcohol or drugs before sex, and having engaged in commercial sex recently. The factors associated with not being aware of one's risk were: being a woman, being from Guyana or Suriname, non-systematic use of condoms with a regular partner, and never or not recently having been tested for HIV. CONCLUSIONS: The results suggest there is still a need for information on HIV risks in a highly vulnerable population.

Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of pazopanib in patients with previously treated advanced GIST. METHODS: In this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400. FINDINGS: Between April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0-37·8) in the pazopanib plus best supportive care group and 28·9 months (22·0-35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1-60·0) in the pazopanib plus best supportive care group versus 17·6% (7·8-30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37-0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4-5·6) with pazopanib plus best supportive care and 2·3 months (2·1-3·3) with best supportive care alone (HR 0·59 [0·37-0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from pazopanib initiation of 3·5 months (95% CI 2·2-5·2). 55 (72%) of the 76 pazopanib-treated patients had pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had pazopanib-related serious adverse events (14 [35%] in the pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not pazopanib-related deaths occurred in the best supportive care group after switch to pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure. INTERPRETATION: Pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients. FUNDING: GlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Léon Bérard.

Is Nephron Sparing Surgery Justified in Wilms Tumor With Beckwith-Wiedemann Syndrome or Isolated Hemihypertrophy?

BACKGROUND: Patients with Beckwith-Wiedemann syndrome (BWS) or isolated hemihypertrophy (HH) treated for a Wilms tumor (WT) carry an increased risk of developing metachronous lesion. There are no guidelines on precise indications for nephron sparing surgery (NSS) in unilateral WT (UWT). The objective of this retrospective study was to delineate the indications of NSS in patients with BWS/HH treated for WT and to evaluate their outcome. PROCEDURE: All cases of BWS/HH treated for a WT according to SIOP protocols from 1980 to 2013 were reviewed. Patients were divided into two groups (G): isolated UWT (G1) and bilateral lesions (G2) with two subgroups: bilateral tumors suspected of malignancy (G2a), and unilateral tumor suspected of malignancy with contralateral nephroblastomatosis (G2b). RESULTS: Forty-six patients were included (34 G1, three G2a, and nine G2b). Nine NSS and 25 total nephrectomies (TN) were performed in G1, two bilateral NSS and one NSS with contralateral TN in G2a, and eight NSS and one TN in G2b. The 3-year event-free survival was 92.3% (95% CI [77.9-97.5%]). One death occurred after a local relapse following a TN for a stage III stromal WT (G1) and another after a combined local and distant relapse following a NSS for a stage I diffuse anaplastic WT (G2b). There were two metachronous WT (4%), 3 years after a TN (G1) and 12 years after a NSS (G2b). CONCLUSIONS: NSS is recommended in bilateral WT and may be an option in selected UWT patients with BWS/HH because it was not associated with an increased risk of local relapse.

The off-label use of targeted therapies in sarcomas: the OUTC'S program.

BACKGROUND: Few targeted therapies (TTs) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after standard treatment escape. The French Sarcoma Group - Bone Tumor Study Group (GSF-GETO) created a national registry to evaluate the outcome of patients treated with off-label TTs. METHODS: Every consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included. The objective was to describe this patient efficacy and safety data in routine practice. RESULTS: From October 2008 to October 2011, 249 patients in 24 centers received 278 treatment lines with TTs. Twenty-five histological subtypes were included: most frequent were leiomyosarcoma (n=48, receiving sorafenib in 63%, and sunitinib in 27%), GIST (n=39, receiving sorafenib in 79%), and angiosarcoma (n=18, receiving sorafenib in 78%). The overall response rate to TTs was 15% (95% CI [10,6-20,2]), the disease control rate at 2 months was 59%. The median progression-free survival was 4,1 months (IC 95% [3,2-4,8]). Three complete responses were observed. No toxic death occurred, grade 3 and 4 toxicities were reported in 74 (27%) and 14 patients (5%) respectively. CONCLUSION: Off-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-randomized clinical trials.

Salvage therapy for refractory or recurrent pediatric germ cell tumors: the French SFCE experience.

PURPOSE: Some children with extracranial germ cell tumors (GCT) relapse after or do not respond to first-line treatment combining chemotherapy and surgery, of whom very few experience long-term survival despite multimodal salvage treatment. METHODS: This prospective study, part of the French TGM95 Protocol for non-seminomatous GCT (NSGCT), included 19 (7%) children with malignant refractory or recurrent extracranial NSGCT who were studied to identify prognostic factors and determine the best salvage treatment. RESULTS: At the end of the first-line treatment, 10 and 9 children were in complete and incomplete remission, respectively. Events occurred within 2 years (5-23 months) after initial diagnosis. A progression was observed in 13 patients at least in one site initially involved. Two patients had a purely biological relapse (increase in isolated markers), and four patients had a purely metastatic relapse (brain location in three cases). After salvage treatment combining surgery and various types of chemotherapy (including high-dose chemotherapy (HDCT) in 10 cases), the 5-year event-free survival and overall survival rates were of 26% (95%CI: 9.6-46.8%) and 32% (95%CI: 12.9-52.2%), respectively. Patients who underwent complete surgery (or without any detectable tumor) had higher survival rate than patients who underwent partial surgery or for whom surgery was not feasible (P = 0.0003) at first relapse while this rate was similar between patients treated or not with HDCT. CONCLUSION: In pediatric recurrent or refractory NSGCT, complete excision of the tumor appears essential. The role of HDCT remains debated.

Territorial inequalities in management and conformity to clinical guidelines for sarcoma patients: an exhaustive population-based cohort analysis in the Rhône-Alpes region.

BACKGROUND: Sarcomas are rare cancers with great variability in clinical and histopathological presentation. The main objective of clinical practice guidelines (CPGs) is to standardize diagnosis and treatment. METHODS: From March 2005 to February 2007, all patients diagnosed with localized sarcoma in the Rhône-Alpes region were included in a cohort-based study, to evaluate the compliance of sarcoma management with French guidelines in routine practice and to identify predictive factors for compliance with CGPs. RESULTS: 634 (71 %) patients with localized sarcoma satisfying the inclusion criteria were included out of 891 newly diagnosed sarcomas. Taking into account initial diagnosis until follow-up, overall conformity to CPGs was only 40 % [95 % confidence interval (CI) = 36-44], ranging from 54 % for gastrointestinal stromal tumor to 36 % for soft tissue sarcoma and 42 % for bone sarcoma. In multivariate analysis, primary tumor type [relative risk (RR) = 4.42, 95 % CI = 2.79-6.99, p < 0.001], dedicated multidisciplinary staff before surgery (RR = 4.19, 95 % CI = 2.39-7.35, p < 0.001) and management in specialized hospitals (RR = 3.71, 95 % CI = 2.43-5.66, p < 0.001) were identified as unique independent risk factors for conformity to CPGs for overall treatment sequence. CONCLUSIONS: With only 40 % of total conformity to CPGs, the conclusions support the improvement of initial sarcoma management and its performance in specialized centres or within specialized dedicated networks.

Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.

BACKGROUND: Brain metastases occur in 30-50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. METHODS: In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m(2), orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov, number NCT00967031. FINDINGS: Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2-27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1-79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. INTERPRETATION: The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. FUNDING: GlaxoSmithKline-France and UNICANCER.

Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study.

PURPOSE: GEMPAX was an open-label, randomized phase III clinical trial designed to assess the efficacy and tolerability of gemcitabine plus paclitaxel versus gemcitabine alone as second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received 5-fluorouracil, oxaliplatin, and irinotecan. METHODS: Patients with histologically or cytologically confirmed mPDAC were randomly assigned (2:1) to receive GEMPAX (paclitaxel 80 mg/m2 + gemcitabine 1,000 mg/m2; IV; once at day (D) 1, D8, and D15/arm A) or gemcitabine (arm B) alone once at D1, D8, and D15 every 28 days until progression, toxicity, or patient's decision. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), quality of life, and safety. RESULTS: Overall, 211 patients (median age, 64 [30-86] years; 62% male) were included. After a median study follow-up for alive patients of 13.4 versus 13.8 months in arm A versus arm B, the median OS (95% CI) was 6.4 (5.2 to 7.4) versus 5.9 months (4.6 to 6.9; hazard ratio [HR], 0.87 [0.63 to 1.20]; P = 0.4095), the median PFS was 3.1 (2.2 to 4.3) versus 2.0 months (1.9 to 2.3; HR, 0.64 [0.47 to 0.89]; P = 0.0067), and the ORR was 17.1% (11.3 to 24.4) versus 4.2% (0.9 to 11.9; P = 0.008) in arm A versus arm B, respectively. Overall, 16.7% of patients in arm A and 2.9% in arm B discontinued their treatment because of adverse events (AEs). One grade 5 AE associated with both gemcitabine and paclitaxel was reported in arm A (acute respiratory distress), and 58.0% versus 27.1% of patients experienced grade ≥3 treatment-related AEs in arm A versus arm B, among which 15.2% versus 4.3% had anemia, 15.9% versus 15.7% had neutropenia, 19.6% versus 4.3% had thrombocytopenia, 10.1% versus 2.9% had asthenia and 12.3% versus 0.0% had neuropathy. CONCLUSION: While GEMPAX did not meet the primary end point of OS versus gemcitabine alone in patients with mPDAC in the second-line setting, both PFS and ORR were significantly improved.

Prevention of sexually transmitted infections among girls and young women in relation to their HPV vaccination status.

BACKGROUND: Having been vaccinated against the human papilloma virus (HPV) may affect other behaviours related to sexual health. This study assessed knowledge and behaviour relevant to the prevention of sexually transmitted infections (STIs) among girls/women aged 14-23 years in relation to their HPV vaccination status. METHODS: From November 2008 to February 2009, 328 girls/women from the Rhône-Alpes region were recruited by general practitioners and completed a self-administered questionnaire. RESULTS: In all, 316 of the 328 respondents provided information on their HPV vaccination status: 135 (42.7%) had been vaccinated (51.2% of girls aged 14-16 years, 44% of women aged 17-20 years and 18.9% of 21-23-year-olds). Knowledge about HPV and the Pap smear was poor overall but greater in those who had been vaccinated: vaccinated 14-16-year-olds were significantly more likely to know the aim of the Pap smear than those not vaccinated (72.7% vs. 41.3%, P < 0.001), and vaccinated 21-23-year-olds were more likely to know about the need to continue Pap smear screening, despite vaccination (60.0% vs. 25.6%, P = 0.06). Irrespective of vaccination status, >80% cited condoms as a means of STI prevention and >85% of those who were sexually active used them. No difference was observed between vaccinated and non-vaccinated groups regarding requests for HIV serology, history of abortions or emergency hormonal contraception. CONCLUSION: Knowledge about cervical cancer prevention was better among those who had been vaccinated against HPV than among those who had not. Knowledge and behaviour relevant to STI prevention seemed appropriate whatever the respondents' vaccination status.

Intra-operative High-Intensity Focused Ultrasound in Patients With Colorectal Liver Metastases: A Prospective Ablate-and-Resect Study.

OBJECTIVE: High-intensity focused ultrasound (HIFU) is a recent, non-ionizing and non-invasive technology of focal destruction. Independence from the heat-sink effect of blood flow makes HIFU an interesting technique for focal ablation of liver tumors. Current available technology is based on extracorporeal treatment that limits use of HIFU for the treatment of liver tumors, as elementary ablations are small and must be juxtaposed to treat tumors, resulting in long-duration treatment. We developed an HIFU probe with toroidal technology, which increases the volume of ablation, for intra-operative use, and we assessed the feasibility and efficacy of this device in patients with colorectal liver metastasis (CLM) measuring less than 30 mm. METHODS: This study was an ablate-and-resect, prospective, single-center, phase II study. All ablations were performed in the area of liver scheduled for liver resection to avoid loss of chance of recovery. The primary objective was to ablate CLM with safety margins (>5 mm). RESULTS: Between May 2014 and July 2020, 15 patients were enrolled and 24 CLM were targeted. The HIFU ablation time was 370 s. In total, 23 of 24 CLM were successfully treated (95.8%). No damage occurred to extrahepatic tissues. HIFU ablations were oblate shaped with an average long axis of 44.3 ± 6.1 mm and an average shortest axis of 35.9 ± 6.7 mm. On pathological examination, the average diameter of the treated metastasis was 12.2 ± 4.8 mm. CONCLUSION: Intra-operative HIFU can safely and accurately produce large ablations in 6 min with real-time guidance (ClinicalTrials.gov identifier: NCT01489787).