Qualitative evaluation of motives for acceptance or refusal of early palliative care in patients included in early-phase clinical trials in a French comprehensive cancer center: the PALPHA study.

PURPOSE: The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient's general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT. METHODS: Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model. RESULTS: Motives for acceptance (PC acceptors: n = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence). CONCLUSIONS: The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management.

Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol.

Background: The clinical management of ependymoma in childhood and adolescence is complex and the clinicobiopathological correlates of outcome remain poorly understood. This international SIOP Ependymoma II (SIOP EPII) trial aims to improve the outcome of patients with ependymoma. Methods: SIOP EPII includes any patient <22 years at diagnosis with ependymoma, stratified by age, tumor location, and outcome of the initial surgery. Centralized pathology and imaging is required for diagnosis confirmation. SIOP EPII included three randomized studies according to age, postoperative residue, and suitability to receive radiotherapy. Patients ineligible for interventional strata are followed-up in an observational study. The staging phase aims to determine if central neurosurgical and radiological postoperative MRI reviews increase the resection rate. Patients ≥12 months with (i) no residual disease are randomly assigned in a phase III trial to evaluate the efficacy of post-radiation 16-week chemotherapy (VEC + CDDP) on PFS (stratum I); (ii) centrally confirmed measurable inoperable residual disease are allocated to randomized frontline chemotherapy phase II study (VEC vs. VEC + high-dose methotrexate) and considered for a second-look surgery (stratum II). If second-look surgery is not feasible or tumor residuum remains, patients receive 8 Gy-boost radiotherapy after conformal radiotherapy (phase I). (iii) Patients < 12 months (18 months in the UK) or not eligible to receive radiotherapy are randomized in a phase II study to receive chemotherapy (alternated myelosuppressive and nonmyelosuppressive chemotherapy), with or without valproate (stratum III). To overcome the limitations encountered in the preliminary conclusions of the ACNS-0831 study, a SIOP EPII dedicated on-study amendment has been planned to definitively conclude the relevance of maintenance chemotherapy in stratum I. Secondary outcomes include overall survival, quality of life, neuropsychological and neuroendocrine outcomes, safety, and identification of key prognostic biomarkers (BIOMECA). Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02265770.

Reasons for acceptance and refusal of early palliative care in patients included in early-phase clinical trials in a regional comprehensive cancer centre in France: protocol for a qualitative study.

INTRODUCTION: A few studies have highlighted the potential synergy between early palliative care and inclusion in an early-phase clinical trial that may improve quality of life, reduce symptoms of exhaustion related to the side effects of treatment and allow patients to complete their treatment protocol. The primary objective of this qualitative study is to evaluate the reasons for acceptance or refusal of early palliative care in patients included in early-phase clinical trials. METHOD AND ANALYSIS: All patients from the Centre Léon Bérard (Comprehensive Cancer Centre in Lyon, France) who consent to one of the early-phase clinical trials proposed at the centre will be invited to participate in this study. The cohort will consist of a subgroup (n=20) of patients who accept palliative care together with their clinical trial, and a second subgroup (n=20) of patients who decline it. Patients will be interviewed in exploratory interviews conducted by a psychology researcher before the start of their clinical trial. The interviews will be audio-recorded. Patients will also be asked to complete quality of life and anxiety/depression questionnaires both before the beginning of the treatment and at the end of their clinical trial. The content of the interviews will be analysed thematically. Descriptive and comparative statistical analysis of both cohorts will also be conducted. ETHICS AND DISSEMINATION: Personal data will be collected and processed in accordance with the laws and regulations in force. All patients will give informed consent to participate. This study complies with reference methodology MR004 of the Commission Nationale de l'Informatique et des Libertés. The protocol has received the validation of an ethics committee (Groupe de Réflexion Ethique du CLB, number: 2020-006). The results will be disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04717440.

Intermittent versus continuous administration of pazopanib in progressive radioiodine refractory thyroid carcinoma: Final results of the randomised, multicenter, open-label phase II trial PAZOTHYR.

INTRODUCTION: Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. PATIENTS AND METHODS: The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. RESULTS: RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2-43.6) best response rate and 89.4% (83.5-93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3-17.4; CP:11.9, 95% CI 7.5-15.6) months (HR 0.79, 0.49-1.27). 6m-SuT rates were similar (IP:80% 66.0-88.7%; CP:78% 63.8-87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8-7.8; CP: 9.2 7.3-11.1) months (HR 1.36, 0.88-2.12). Pazopanib-related adverse events grade 3-4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. CONCLUSIONS: Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov, number NCT01813136.

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23.

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.

Monitoring shot-to-shot variations of soft x-ray sources using aluminum foils.

We report a straightforward beam splitter in the soft x-ray spectral range using a thin oxidized aluminum foil. As it allows us to monitor reliably shot-to-shot variations in energy and in energy distribution, this beam splitter is of high interest for the simultaneous use of diagnostics for soft x-rays sources. We measure a transmission of 0.5 and a reflectivity of 0.018 at 22.5° of incidence with a soft x-ray laser working at 32.8 nm. These values are in good agreement with the theory. As the theory predicts a reflectivity and a transmission of both 12% at 52.5° of incidence for 32.8 nm, it can also be useful for experiments that require the division and recombination of a beam, for instance, interferometry or pump-probe technique with an intense soft x-ray source.

High mortality rate in cancer patients with symptoms of COVID-19 with or without detectable SARS-COV-2 on RT-PCR.

BACKGROUND: Cancer patients presenting with COVID-19 have a high risk of death. In this work, predictive factors for survival in cancer patients with suspected SARS-COV-2 infection were investigated. METHODS: PRE-COVID-19 is a retrospective study of all 302 cancer patients presenting to this institute with a suspicion of COVID-19 from March 1st to April 25th 2020. Data were collected using a web-based tool within electronic patient record approved by the Institutional Review Board. Patient characteristics symptoms and survival were collected and compared in SARS-COV-2 real-time or reverse-transcriptase PCR (RT-PCR)-positive and RT-PCR-negative patients. RESULTS: Fifty-five of the 302 (18.2%) patients with suspected COVID-19 had detectable SARS-COV-2 with RT-PCR in nasopharyngeal samples. RT-PCR-positive patients were older, had more frequently haematological malignancies, respiratory symptoms and suspected COVID-19 pneumonia of computed tomography (CT) scan. However, respectively, 38% and 20% of SARS-COV-2 RT-PCR-negative patients presented similar respiratory symptoms and CT scan images. Thirty of the 302 (9.9%) patients died during the observation period, including 24 (80%) with advanced disease. At the median follow-up of 25 days after the first symptoms, the death rate in RT-PCR-positive and RT-PCR-negative patients were 21% and 10%, respectively. In both groups, independent risk factors for death were male gender, Karnofsky performance status <60, cancer in relapse and respiratory symptoms. Detection of SARS-COV-2 on RT-PCR was not associated with an increased death rate (p = 0.10). None of the treatment given in the previous month (including cytotoxics, PD1 Ab, anti-CD20, VEGFR2…) correlated with survival. The survival of RT-PCR-positive and -negative patients with respiratory symptoms and/or COVID-19 type pneumonia on CT scan was similar with a 18.4% and 19.7% death rate at day 25. Most (22/30, 73%) cancer patients dying during this period were RT-PCR negative. CONCLUSION: The 30-day death rate of cancer patients with or without documented SARS-COV-2 infection is poor, but the majority of deaths occur in RT-PCR-negative patients.

PALLIA-10, a screening tool to identify patients needing palliative care referral in comprehensive cancer centers: A prospective multicentric study (PREPA-10).

PURPOSE: The identification and referral of patients in need of palliative care should be improved. The French society for palliative support and care recommended to use the PALLIA-10 questionnaire and its score greater than 3 to refer patients to palliative care. We explored the use of the PALLIA-10 questionnaire and its related score in a population of advanced cancer patients. METHODS: This prospective multicentric study is to be conducted in authorized French comprehensive cancer centers on hospitalized patients on a given day. We aimed to use the PALLIA-10 score to determine the proportion of palliative patients with a score >3. Main secondary endpoints were to determine the proportion of patients already managed by palliative care teams at the study date or referred to palliative care in six following months, the prevalence of patients with a score greater than 5, and the overall survival using the predefined thresholds of 3 and 5. RESULTS: In 2015, eighteen French cancer centers enrolled 840 patients, including 687 (82%) palliative patients. 479 (69.5%) patients had a score >3, 230 (33.5%) had a score >5, 216 (31.4%) patients were already followed-up by a palliative care team, 152 patients were finally referred to PC in the six subsequent months. The PALLIA-10 score appeared as a reliable predictive (adjusted ORRef≤3 : 1.9 [1.17-3.16] and 3.59 [2.18-5.91]) and prognostic (adjusted HRRef≤3  = 1.58 [95%CI 1.20-2.08] and 2.18 [95%CI 1.63-2.92]) factor for patients scored 4-5 and >5, respectively. CONCLUSION: The PALLIA-10 questionnaire is an easy-to-use tool to refer cancer inpatients to palliative care in current practice. However a score greater than 5 using the PALLIA-10 questionnaire would be more appropriate for advanced cancer patients hospitalized in comprehensive cancer center.

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.