当前期刊: European Journal of Cancer Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Tumour-infiltrating lymphocytes (TILs) and BRCA-like status in stage III breast cancer patients randomised to adjuvant intensified platinum-based chemotherapy versus conventional chemotherapy
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-16
    Leonora de Boo; Ashley Cimino-Mathews; Yoni Lubeck; Antonios Daletzakis; Mark Opdam; Joyce Sanders; Erik Hooijberg; Annelot van Rossum; Zuzana Loncova; Dietmar Rieder; Zlatko Trajanoski; Marieke Vollebergh; Marcelo Sobral-Leite; Koen van de Vijver; Annegien Broeks; Rianne van der Wiel; Harm van Tinteren; Sabine Linn; Marleen Kok

    Background The prognostic value of tumour-infiltrating lymphocytes (TILs) differs by breast cancer (BC) subtype. The aim of this study was to evaluate TILs in stage III BC in the context of BRCA1/2-like phenotypes and association with outcome and benefit of intensified platinum-based chemotherapy. Patients and methods Patients participated in a randomised controlled trial of adjuvant intensified platinum-based chemotherapy versus conventional anthracycline-based chemotherapy carried out between 1993 and 1999 in stage III BC. Stromal TILs were scored according to International guidelines in these human epidermal growth factor receptor 2 (HER2)-negative tumours. BRCA-profiles were determined using Comparative Genomic Hybridization. Results TIL levels were evaluated in 248 BCs. High TILs were associated with Triple Negative BC (TNBC). BRCA-like tumours harboured higher TILs compared to non-BRCA-like tumours (median TILs of 20% versus 10%, p < 0.01). TIL levels in BRCA1-like tumours were higher compared to BRCA2-like tumours (median TILs of 20% versus 10%, p < 0.001). These correlations remained significant within the oestrogen (ER)-positive subgroup, however not within the TNBC subgroup. In this stage III BC cohort, high TIL level was associated with favourable outcome (TILs per 10% increment, recurrence-free survival (RFS): multivariate hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71–0.94, p = 0.01; overall survival (OS): multivariate HR 0.80, 95% CI 0.68–0.94, p = 0.01). There was no significant interaction between TILs and benefit of intensified platinum-based chemotherapy. Conclusion In this high-risk breast cancer cohort, high TILs were associated with TNBC and BRCA1-like status. Within the ER-positive subgroup, TIL levels were higher in BRCA1-like compared to BRCA2-like tumours. When adjusted for clinical characteristics, TILs were significantly associated with a more favourable outcome in stage III BC patients.

    更新日期:2020-01-16
  • Randomised phase II trial evaluating the safety of peripherally inserted catheters versus implanted port catheters during adjuvant chemotherapy in patients with early breast cancer
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-10
    Florian Clatot; Maxime Fontanilles; Laureline Lefebvre; Justine Lequesne; Corinne Veyret; Cristina Alexandru; Marianne Leheurteur; Cécile Guillemet; Sophie Gouérant; Camille Petrau; Jean-Christophe Théry; Olivier Rigal; Cristian Moldovan; Isabelle Tennevet; Olivier Rastelli; Amélie Poullain; Laetitia Savary; Michael Bubenheim; Frédéric Di Fiore

    Background Both peripherally inserted central catheters (PICCs) and implanted port catheters (PORTs) are used for adjuvant chemotherapy (ACT) administration in patients with early breast cancer (EBC). We aimed to compare the safety between PICCs and PORTs in this setting. Patients and methods This monocentric phase II randomised trial (NCT02095743) included patients with EBC who were eligible for ACT. Patients with curative anticoagulation therapy were excluded. The primary objective was to identify which device has a lower probability of catheter-related significant adverse events (CR-SAEs) within the 35 weeks after device implantation. The secondary objective was to evaluate quality of life (QoL) and patient satisfaction. Results From February 2014 to May 2018, 256 patients were included, and 253 (99%) were analysed. Overall, 31 patients (12.2%) experienced CR-SAEs, which mainly included thromboembolic events. In an intention-to-treat analysis, the probability that a CR-SAE would occur was 7.8% (10 events) with PORTs versus 16.6% (21 events) with PICCs (hazard ratio [HR] = 2.2 [1.03–4.62], P = 0.036). In a per-protocol analysis, PICCs were also associated with a higher risk of CR-SAEs than PORTs (HR = 2.82 [1.26–6.25], P = 0.007). Regarding the secondary objectives, if there was no difference in QoL between the arms, then significantly more discomfort was reported among patients with PICCs than among patients with PORTs (P = 0.002 after implantation and P < 0.001 at mid-treatment or at the end of treatment). Conclusions CR-SAEs in patients with EBC are frequent but rarely impact the ACT process. Compared with PORTs, PICCs are associated with a significantly higher risk of CR-SAEs and more discomfort. PORTs should be preferred for ACT administration in patients with EBC.

    更新日期:2020-01-11
  • The CXCR2/CXCL2 signalling pathway – An alternative therapeutic approach in high-grade glioma
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-09
    Güliz Acker; Julia Zollfrank; Claudius Jelgersma; Melina Nieminen-Kelhä; Irina Kremenetskaia; Susanne Mueller; Adnan Ghori; Peter Vajkoczy; Susan Brandenburg

    Objective Besides VEGF, alternative signalling via CXCR2 and its ligands CXCL2/CXCL8 is a crucial part of angiogenesis in glioblastoma. Our aim was to understand the role of CXCR2 for glioma biology and elucidate the therapeutic potential of its specific inhibition. Methods GL261 glioma cells were implanted intracranially in syngeneic mice. The 14 or 7 days of local or systemic treatment with CXCR2-antagonist (SB225002) was initiated early on the day of tumour cell implantation or delayed after 14 days of tumour growth. Glioma volume was verified using MRI before and after treatment. Immunofluorescence staining was used to investigate tumour progression, angiogenesis and microglial behaviour. Furthermore, in vitro assays and gene expression analyses of glioma and endothelial cells were performed to validate inhibitor activity. Results CXCR2-blocking led to significantly reduced glioma volumes of around 50% after early and delayed local treatments. The treated tumours were comparable with controls regarding invasiveness, proliferation and apoptotic cell activity. Furthermore, no differences in CXCR2/CXCL2 expression were observed. However, immunostaining revealed reduction in vessel density and accumulation of microglia/macrophages, whereas interaction of these myeloid cells with tumour vessels was enhanced. In vitro analyses of the CXCR2-antagonist showed its direct impact on proliferation of glioma and endothelial cells if used at higher concentrations. In addition, expression of CXCR2/CXCL2 signalling genes was increased in both cell types by SB225002, but VEGF-relevant genes were unaffected. Conclusion The CXCR2-antagonist inhibited glioma growth during tumour initiation and progression, whereas treatment was well-tolerated by the recipients. Thus, the CXCR2/CXCL2 signalling represents a promising therapeutic target in glioma.

    更新日期:2020-01-11
  • JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-09
    Tina Bagratuni; Nefeli Mavrianou; Nikolaos G. Gavalas; Kimon Tzannis; Calliope Arapinis; Michael Liontos; Maria I. Christodoulou; Nikolaos Thomakos; Dimitrios Haidopoulos; Alexandros Rodolakis; Efstathios Kastritis; Andreas Scorilas; Meletios A. Dimopoulos; Aristotle Bamias

    Background Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types. Results Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Μyc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively. Conclusion Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease.

    更新日期:2020-01-11
  • Impact of colorectal cancer screening on cancer-specific mortality in Europe: A systematic review
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-10
    Andrea Gini; Erik E.L. Jansen; Nadine Zielonke; Reinier G.S. Meester; Carlo Senore; Ahti Anttila; Nereo Segnan; Dominika Novak Mlakar; Harry J. de Koning; Iris Lansdorp-Vogelaar

    Background Populations differ with respect to their cancer risk and screening preferences, which may influence the performance of colorectal cancer (CRC) screening programs. This review aims to systematically compare the mortality effect of CRC screening across European regions. Methods Six databases including Embase, Medline, Web of Science, PubMed publisher, Google Scholar and Cochrane Library were searched for relevant studies published before March 2018. Bibliographic searches were conducted to select studies assessing the effect of various screening tests (guaiac fecal occult blood test [gFOBT]; flexible sigmoidoscopy [FS]; fecal immunochemical test [FIT] and colonoscopy) on CRC mortality in Europe (PROSPERO protocol: CRD42016042433). Abstract reviewing, data extraction and risk of bias assessment were conducted independently by two reviewers. Results A total of 18 studies were included; of which, 11 were related to gFOBT, 4 to FS, 2 to FIT and 1 to colonoscopy; 8 were randomised clinical trials, and 10, observational studies, and an approximately equal number of studies represented Northern, Western and Southern European regions. Among individuals invited to screening, CRC mortality reductions varied from 8% to 16% for gFOBT and from 21% to 30% for FS. When studies with a high risk of bias were considered, ranges were more extensive. The estimated effectiveness of gFOBT and FS screening appeared similar across different European regions. Conclusions CRC mortality impact of inviting individuals with similar adopted screening strategies (gFOBT or FS) may be consistent across several European settings.

    更新日期:2020-01-11
  • Evidence for reducing cancer-specific mortality due to screening for breast cancer in Europe: A systematic review
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-10
    Nadine Zielonke; Andrea Gini; Erik E.L. Jansen; Ahti Anttila; Nereo Segnan; Antonio Ponti; Piret Veerus; Harry J. de Koning; Nicolien T. van Ravesteyn; Eveline A.M. Heijnsdijk

    Background The aim of this study was to quantify the impact of organised mammography screening on breast cancer mortality across European regions. Therefore, a systematic review was performed including different types of studies from all European regions and stringently used clearly defined quality appraisal to summarise the best evidence. Methods Six databases were searched including Embase, Medline and Web of Science from inception to March 2018. To identify all eligible studies which assessed the effect of organised screening on breast cancer mortality, two reviewers independently applied predefined inclusion and exclusion criteria. Original studies in English with a minimum follow-up of five years that were randomised controlled trials (RCTs) or observational studies were included. The Cochrane risk of bias instrument and the Newcastle–Ottawa Scale were used to assess the risk of bias. Results Of the 5015 references initially retrieved, 60 were included in the final analysis. Those comprised 36 cohort studies, 17 case–control studies and 7 RCTs. None were from Eastern Europe. The quality of the included studies varied: Nineteen of these studies were of very good or good quality. Of those, the reduction in breast cancer mortality in attenders versus non-attenders ranged between 33% and 43% (Northern Europe), 43%–45% (Southern Europe) and 12%–58% (Western Europe). The estimates ranged between 4% and 31% in invited versus non-invited. Conclusion This systematic review provides evidence that organised screening reduces breast cancer mortality in all European regions where screening was implemented and monitored, while quantification is still lacking for Eastern Europe. The wide range of estimates indicates large differences in the evaluation designs between studies, rather than in the effectiveness of screening.

    更新日期:2020-01-11
  • European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics – Update 2019
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-09
    Claus Garbe; Teresa Amaral; Ketty Peris; Axel Hauschild; Petr Arenberger; Lars Bastholt; Veronique Bataille; Veronique del Marmol; Brigitte Dréno; Maria Concetta Fargnoli; Jean-Jacques Grob; Christoph Höller; Roland Kaufmann; Aimilios Lallas; Celeste Lebbé; Josep Malvehy; Mark Middleton; David Moreno-Ramirez; Alexander M.M. Eggermont

    Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed through dermatoscopy. If a melanoma is suspected, a histopathological examination is required. Sequential digital dermatoscopy and full-body photography can be used in risk persons to detect the development of melanomas at an earlier stage. Where available, confocal reflectance microscopy can improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the AJCC classification. Thin melanomas up to 0.8 mm tumor thickness does not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC whole-body examinations with CT or PET-CT in combination with brain MRI are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to support the frequency and extent of examinations. A stage-based follow-up scheme is proposed, which, according to the experience of the guideline group, covers the minimum requirements; further studies may be considered. This guideline is valid until the end of 2021.

    更新日期:2020-01-11
  • Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-09
    Didier Decaudin; Estelle Frisch Dit Leitz; Fariba Nemati; Malcy Tarin; Adnan Naguez; Mohamed Zerara; Benjamin Marande; Raquel Vivet-Noguer; Ensar Halilovic; Claire Fabre; Aart Jochemsen; Sergio Roman-Roman; Samar Alsafadi

    Introduction Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available. Methodology To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs). Results We demonstrated that the Bcl-2/XL/W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of ABT263 with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect. Conclusion We showed that inhibition of Bcl-2/XL/W sensitised the UM cell lines to other treatments encouraging investigation of the underlying mechanisms. Furthermore, our findings highlighted Bcl-2/XL/W and MDM2 co-inhibition as a promising strategy in UM.

    更新日期:2020-01-09
  • Positron-emission tomography–based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-08
    Connie L. Batlevi; Fushen Sha; Anna Alperovich; Ai Ni; Katy Smith; Zhitao Ying; John F. Gerecitano; Paul A. Hamlin; Steve M. Horwitz; Erel Joffe; Anita Kumar; Matthew J. Matasar; Alison J. Moskowitz; Craig H. Moskowitz; Ariela Noy; Colette Owens; Lia M. Palomba; David Straus; Anas Younes

    Background Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods In this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Results In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. Conclusion In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy.

    更新日期:2020-01-08
  • Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: Pooled analysis in advanced HER2-positive breast cancer
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-07
    Noam Pondé; Lieveke Amaye; Matteo Lambertini; Marianne Paesmans; Martine Piccart; Evandro de Azambuja

    Introduction T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. Methods We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. Results Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%–4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77–5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29–5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. Conclusion The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.

    更新日期:2020-01-07
  • A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib in non-adipocytic patients previously treated with both chemotherapy and pazopanib
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-06
    Nicolas Penel; Olivier Mir; Jennifer Wallet; Isabelle Ray-Coquard; Axel Le Cesne; Antoine Italiano; Sebastien Salas; Corinne Delcambre; Emmanuelle Bompas; François Bertucci; Esma Saada-Bouzid; Loïc Chaigneau; Christine Chevreau; Thomas Brodowicz; Emilie Decoupigny; Marie Vanseymortier; Lucie Laroche; Sophie Taieb; Jean-Yves Blay

    Background Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. Patients and methods This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours–based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). Results From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4–not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15–0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23–1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). Conclusion The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

    更新日期:2020-01-07
  • Cervical cancer mortality in young adult European women
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-06
    Cezary Wojtyla; Kinga Janik-Koncewicz; Carlo La Vecchia

    Background The process of social, political and economic transformation, which took place in Central and Eastern Europe in the early 90's, has affected many spheres of Europeans' lives, including health-associated issues. These changes also had an impact on mortality rates due to cervical cancer (CC). Therefore, the aim of this study was to analyse CC mortality trends in Europe after 1990. Methods Data on death due to CC, uterine cancers and unspecified uterine cancers, in women aged 20–44, were taken from the WHO Mortality Database. Trends in European countries between 1990 and 2017 were assessed using the Joinpoint Regression Program. Results Most of the countries experienced a decrease in CC mortality. Although the lowest rates were observed in EU15 Member States, the highest decreases were observed in Central and Eastern Europe. However, there are still differences in mortality in these countries. There are also a few countries like Belarus, Latvia and Ukraine, which experienced an increase in mortality. The range of mortality across Europe in 2017 was between 0.6 and 5.2/100,000 women. Conclusions It is essential to introduce well-organised screening programmes for early detection of CC with coverage of a correspondingly high percentage of the population, particularly in East-Central Europe, as well as to introduce high-coverage HPV vaccination in all European countries.

    更新日期:2020-01-07
  • Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600–mutant melanoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-02
    Paolo A. Ascierto; Reinhard Dummer; Helen J. Gogas; Keith T. Flaherty; Ana Arance; Mario Mandala; Gabriella Liszkay; Claus Garbe; Dirk Schadendorf; Ivana Krajsova; Ralf Gutzmer; Jan Willem B. de Groot; Carmen Loquai; Ashwin Gollerkeri; Michael D. Pickard; Caroline Robert

    Background BRAF/MEK inhibitor combinations are established treatments for BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. Methods In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. Results At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4–39.2) for COMBO450, 23.5 months (95% CI, 19.6–33.6) for ENCO300 and 16.9 months (95% CI, 14.0–24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48–0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0–20.2), ENCO300 was 9.6 months (95% CI, 7.4–14.8) and VEM was 7.3 months (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39–0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. Conclusions Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600–mutated melanoma.

    更新日期:2020-01-02
  • A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-31
    Gregory M. Cote; Edwin Choy; Tianqi Chen; Adrian Marino-Enriquez; Jeffrey Morgan; Priscilla Merriam; Katherine Thornton; Andrew J. Wagner; Michael J. Nathenson; George Demetri; Suzanne George

    Chemotherapy objective response rates (ORRs) in metastatic soft tissue sarcoma (STS) are typically 20–40% with median progression-free survival (PFS) less than 6 months. Lurbinectedin is a new anticancer agent under investigation. The primary objective of this three-arm, phase II study was to determine the disease control rate (DCR = ORR + stable disease [SD]) at 24 weeks of lurbinectedin alone or with chemotherapy in STS. Eligible patients included adults with ≤2 prior cytotoxic therapies. Study cohorts were: stratum A (StrA; anthracycline-naive), lurbinectedin/doxorubicin; stratum B (StrB; prior anthracycline), lurbinectedin/gemcitabine; stratum C (StrC; prior anthracycline/gemcitabine) lurbinectedin monotherapy. Each stratum was analysed separately by Simon two-stage design. Forty-two patients were accrued (StrA = 20, StrB = 10, StrC = 12) including leiomyosarcoma [LMS] (n = 20), synovial sarcoma [SS](n = 4), malignant peripheral nerve sheath tumour (n = 3) and other STS histologies (n = 15). For StrA there were seven partial responses (PR) plus one stable disease (SD) at 24 weeks. For StrB, two patients met the 24-week DCR including one PR (leiomyosarcoma) and one SD (desmoplastic small round cell tumour [DSRCT]). StrB did not continue to the second stage. In StrC, no patients met the primary end-point. Median progression-free survival (PFS) was: StrA = 4.2 months (90% CI 1.4–7.8), StrB = 1.7 months (90% confidence interval (CI) 1.0–7.4), and StrC = 1.3 months (90% CI 1.1–3.0). Lurbinectedin as a single agent or with chemotherapy was well tolerated with haematologic adverse events (AE's) as the most common toxicity. There were no treatment-related deaths. The combination of lurbinectedin/doxorubicin reached the DCR end-point with seven PR and one patient with SD (ORR 35.0%, 24-week DCR 40.0%). Evidence of drug benefit was seen in leiomyosarcoma, dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), synovial sarcoma (SS), and desmoplastic small round cell tumour (DSRCT). Trial registration clinicaltrials.gov; NCT02448537

    更新日期:2019-12-31
  • Molecular imaging to identify patients with metastatic breast cancer who benefit from endocrine treatment combined with cyclin-dependent kinase inhibition
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-28
    Jorianne Boers; Clasina M. Venema; Erik F.J. de Vries; Andor W.J.M. Glaudemans; Thomas C. Kwee; Ed Schuuring; John W.M. Martens; Sjoerd G. Elias; Geke A.P. Hospers; Carolina P. Schröder

    Background Adding cyclin-dependent kinase (CDK) inhibitor to endocrine treatment improves outcome in œstrogen receptor (ER) positive metastatic breast cancer, but identifying the subset of patients who benefit is challenging. Response is potentially associated with ER expression heterogeneity. This is because, unlike the primary tumour in the breast that is localized to the organ, the metastatic breast cancer has spread and continues to spread to distant locations in the body such as bones, lungs, liver, axial skeleton, even to the central nervous system like the brain, wherefrom obtaining biopsies are not easy, and also, the metastasised tissues are heterogeneous. Positron emission tomography (PET) with 16α-[18F]fluoro-17β-œstradiol (FES), briefly referred to as FES-PET, allows whole-body ER assessment. We explored whether FES-PET heterogeneity and FES uptake were related to letrozole and palbociclib outcome, in patients with ER positive, metastatic breast cancer. Patients and methods Patients underwent a baseline FES-PET and 18F-fluorodeoxyglucose (FDG) PET, the FDG-PET served to help identify active sites of breast cancer with contrast-enhanced computed tomography (CT). FES-PET heterogeneity score (% FES positive lesions divided by all lesions on FDG-PET and/or CT) and FES uptake were related to outcome and 8-week FDG-PET response. Circulating tumour DNA (CtDNA) samples for ESR1 mutation analysis were collected at baseline. Results In 30 patients with 864 metastatic lesions, baseline FES-PET heterogeneity was assessed. In 27 patients with 688 lesions, response was evaluated. Median time to progression (TTP) was 73 weeks (95% confidence interval [CI] 21 to ∞) in 7 patients with 100% FES positive disease, 27 weeks (14–49) in heterogeneous FES positive disease (20 patients), and 15 weeks (9 to ∞) without FES positivity (three patients; log-rank P = 0.30). Geometric mean FES uptake was 2.3 for metabolic progressive patients, 2.5 (Pvs progression = 0.82) for metabolic stable disease, and 3.3 (Pvs progression = 0.40) for metabolic response (Ptrend = 0.21). ESR1 mutations, found in 13/23 patients, were unrelated to FES uptake. Conclusion This exploratory study suggests that FES-PET heterogeneity may potentially identify the subset of ER positive, metastatic breast cancer patients who benefit from letrozole combined with CDK inhibition. Clinical trial information NCT02806050.

    更新日期:2019-12-29
  • Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-27
    Frede Donskov; Robert J. Motzer; Eric Voog; Elizabeth Hovey; Carsten Grüllich; Louise M. Nott; Katharine Cuff; Thierry Gil; Niels Viggo Jensen; Christine Chevreau; Sylvie Negrier; Reinhard Depenbusch; Lothar Bergmann; Izzy Cornelio; Anne Champsaur; Bernard Escudier; Sumanta Pal; Thomas Powles; Toni K. Choueiri

    Background Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC. Methods Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n = 394), 65–74 (n = 201) and ≥75 years (n = 63). Results PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41–0.68), 0.53 (95% CI: 0.37–0.77) and 0.38 (95% CI: 0.18–0.79) for <65, 65–74 and ≥75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54–0.95), 0.66 (95% CI: 0.44–0.99) and 0.57 (95% CI: 0.28–1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups. Conclusions Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy.

    更新日期:2019-12-29
  • European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment – Update 2019
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-19
    Claus Garbe; Teresa Amaral; Ketty Peris; Axel Hauschild; Petr Arenberger; Lars Bastholt; Veronique Bataille; Veronique del Marmol; Brigitte Dréno; Maria Concetta Fargnoli; Jean-Jacques Grob; Christoph Höller; Roland Kaufmann; Aimilios Lallas; Celeste Lebbé; Josep Malvehy; Mark Middleton; David Moreno-Ramirez; Alexander M.M. Eggermont

    A unique collaboration of multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with 1- to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumour thickness ≥1.0 mm or ≥0.8 mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team (“Tumor Board”). Adjuvant therapies in stage III/IV patients are primarily anti–PD-1, independent of mutational status, or dabrafenib plus trametinib for BRAF-mutant patients. In distant metastasis, either resected or not, systemic treatment is indicated. For first-line treatment, particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In particular scenarios for patients with stage IV melanoma and a BRAF-V600 E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy. In patients with primary resistance to immunotherapy and harbouring a BRAF-V600 E/K mutation, this therapy shall be offered in second-line. Systemic therapy in stage III/IV melanoma is a rapidly changing landscape, and it is likely that these recommendations may change in the near future.

    更新日期:2019-12-19
  • Suicide death among cancer patients: new data from northern Italy, systematic review of the last 22 years and meta-analysis
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-18
    Alessandra Ravaioli; Emanuele Crocetti; Silvia Mancini; Flavia Baldacchini; Orietta Giuliani; Rosa Vattiato; Lauro Bucchi; Fabio Falcini

    Background An increased risk of death by suicide in cancer patients has been documented since decades. We evaluated the risk of death by suicide in an Italian population-based cancer case series and added the results to a systematic review and meta-analysis of the literature. Methods The Italian series, including 127,042 primary cancer patients diagnosed between 1996 and 2014, was obtained from the Romagna Cancer Registry (northern Italy). Standardised mortality ratios (SMRs) were calculated. Regarding the systematic review and meta-analysis, the PubMed database was searched for English language studies published up to 2017. Fifty-seven potentially eligible papers were reviewed in full, and 19 of them were selected for analysis. The SMR was the first outcome, replaced by rate ratio if the SMR was not available. Findings In the Italian case series, an increased suicide risk was found for both sexes combined (SMR = 1.5; 95% confidence interval [CI]: 1.3–1.8), for males (SMR = 1.6; 95% CI: 1.4–1.9) but not females (SMR = 1.1; 95% CI: 0.7–1.7), for patients aged ≥55 years, with poor prognosis and advanced-stage disease and during the first year after diagnosis. The absolute excess risk of suicide was 0.9 per 10,000 patient-years. Multivariate analysis confirmed the role of univariate factors except for poor prognosis. Meta-analysis showed a strong heterogeneity between studies. The risk was significantly elevated for both sexes combined (pooled SMR = 1.7; 95% CI: 1.5–1.9), men (pooled SMR = 1.8; 95% CI: 1.6–2.0) and women (pooled SMR = 1.4; 95% CI: 1.3–1.6). There was no evidence for small-study effects. Interpretation The Italian study confirmed the previous common finding that cancer patients are at increased risk for suicide. A clinical multidisciplinary approach to support them is needed.

    更新日期:2019-12-18
  • Effectiveness of intensive clinical and radiological follow-up in patients with surgically resected NSCLC. Analysis of 2661 patients from the prospective MAGRIT trial
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-13
    Fabio Conforti; Laura Pala; Eleonora Pagan; Vincenzo Bagnardi; Paola Zagami; Lorenzo Spaggiari; Chiara Catania; Johan Vansteenkiste; Giuseppe Giaccone; Tommaso De Pas

    Background Limited evidence is available on effectiveness of clinicoradiological follow-up of early-stage NSCLC patients. MAGRIT was a phase III adjuvant RCT conducted in surgically resected stage IB-IIIA NSCLC patients, in which all participants had a prospectively defined intensive clinicoradiological follow-up. Methods At patient-level data, we analyzed detection modality of disease recurrences and new primary lung cancer (i.e. detected by clinicoradiological scheduled exams versus by interim unscheduled exams), features associated with higher risk of locoregional and/or distant recurrence, and recurrence rates over time. Results In the 2261 patients studied, there was a significant association between the type of recurrence and the modality of detection: 88.4% (95% CI, 84%–91%) of the locoregional recurrences and 93.2% (95% CI, 84%–99%) of the new primary lung cancers were detected by scheduled exams, whereas this was only 68.7% (95% CI, 65%–73%) for distant metastases (p < 0.001). Survival of patients with locoregional recurrence or new primary lung cancer detected by scheduled exams was significantly better as compared with those detected by unscheduled exams (HR 0.56, 95% CI 0.36–0.87; p = 0.01). Survival was similarly poor in patients with distant recurrences, both with scheduled and unscheduled detection (3-year survival after recurrence 22.0% and 21.8%, respectively). Recurrence rate was the highest in the first 18 months after surgery—with a peak between month 6 and 12—decreasing thereafter. The hazard of a second primary lung cancer was constant over time. Conclusion Intensive follow-up is effective in detecting locoregional recurrences and second primary lung cancers, with impact on patients’ survival but did not influence the detection of distant recurrences.

    更新日期:2019-12-17
  • Nationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-13
    Anouk E.J. Latenstein; Lydia G.M. van der Geest; Bert A. Bonsing; Bas Groot Koerkamp; Nadia Haj Mohammad; Ignace H.J.T. de Hingh; Vincent E. de Meijer; Izaak Q. Molenaar; Hjalmar C. van Santvoort; Geertjan van Tienhoven; Joanne Verheij; Pauline A.J. Vissers; Judith de Vos-Geelen; Olivier R. Busch; Casper H.J. van Eijck; Hanneke W.M. van Laarhoven; Marc G. Besselink; Johanna W. Wilmink

    Background In recent years, new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC) including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin. The impact hereof has not been assessed in nationwide cohort studies. This population-based study aimed to investigate nationwide trends in incidence, treatment and survival of PDAC. Materials and methods Patients with PDAC (1997–2016) were included from the Netherlands Cancer Registry. Results were categorised by treatment and by period of diagnosis (1997–2000, 2001–2004, 2005–2008, 2009–2012 and 2013–2016). Kaplan–Meier survival analysis was used to calculate overall survival. Results In a national cohort of 36,453 patients with PDAC, the incidence increased from 12.1 (1997–2000) to 15.3 (2013–2016) per 100,000 (p < 0.001), whereas median overall survival increased from 3.1 to 3.8 months (p < 0.001). Over time, the resection rate doubled (8.3%–16.6%, p-trend<0.001), more patients received adjuvant chemotherapy (3.0%–56.2%, p-trend<0.001) and 3-year overall survival following resection increased (16.9%–25.4%, p < 0.001). Over time, the proportion of patients with metastatic disease who received palliative chemotherapy increased from 5.3% to 16.1% (p-trend<0.001), whereas 1-year survival improved from 13.3% to 21.2% (p < 0.001). The proportion of patients who only received supportive care decreased from 84% to 61% (p-trend<0.001). Conclusion The incidence of PDAC increased in the past two decades. Resection rates and use of adjuvant or palliative chemotherapy increased with improved survival in these patients. In all patients with PDAC, however, the survival benefit of 3 weeks is negligible because the majority of patients only received supportive care.

    更新日期:2019-12-17
  • Reference values for the EORTC QLQ-C30 in early and metastatic breast cancer
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-12
    Justyna Mierzynska; Mekdes Taye; Madeline Pe; Corneel Coens; Francesca Martinelli; Katarzyna Pogoda; Galina Velikova; Vesna Bjelic-Radisic; Fatima Cardoso; Etienne Brain; Michail Ignatiadis; Martine Piccart; Geertjan Van Tienhoven; Robert Mansel; Hans Wildiers; Andrew Bottomley

    Background Considering the worldwide incidence of breast cancer (BC) and the importance of health-related quality of life (HRQoL) assessment, there is a growing need to have accurate and up-to-date reference values (RVs). RVs are useful for the design of randomised controlled trials (RCTs) and as benchmarks for comparison of cancer RCTs and health care interventions. This study aimed to provide RVs for the QLQ-C30 in early BC (EBC) and metastatic BC (MBC). General patterns of main results from the EORTC dataset (main dataset) were compared with the PDS dataset (comparison dataset) to see whether they would be consistent across pre-defined covariates. Methods European Organization for Research and Treatment of Cancer (EORTC) (main dataset) and Project Data Sphere (PDS) (comparison dataset) were searched to identify BC RCTs where baseline HRQoL (before treatment) was assessed with the QLQ-C30. RVs were calculated and stratified by disease stage, age, and when available, performance status (PS), comorbidity and region. RVs were reported using descriptive statistics. Results Data from three EORTC (n = 4115) and three PDS RCTs (n = 1406) were included in the analysis. While EBC patients presented better HRQoL with high baseline functioning scores and low prevalence of symptoms, MBC patients reported worse HRQoL with lower functioning scores and more prevalence of symptoms. In MBC, poor PS and presence of comorbidities reflected worse baseline HRQoL. No consistent differences were found for age and countries. Conclusion These up-to-date RVs for the EORTC QLQ-C30 in BC show differences in HRQoL scores between stages, PS, and comorbidities. These findings, supported by an independent dataset, will help the clinical interpretation of scores for BCpatients.

    更新日期:2019-12-13
  • Patient-reported outcomes from FLAURA: Osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small-cell lung cancer
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-12
    Natasha B. Leighl; Nina Karaseva; Kazuhiko Nakagawa; Byoung-Chul Cho; Jhanelle E. Gray; Tina Hovey; Andrew Walding; Anna Rydén; Silvia Novello

    Background In the FLAURA trial, osimertinib demonstrated superior progression-free survival and a favorable toxicity profile to erlotinib or gefitinib as initial therapy in patients with EGFR-mutated advanced non-small-cell lung cancer. Patient-reported outcomes from FLAURA are discussed here. Methods Patients (N = 556) completed the EORTC QLQ-LC13 weekly for 6 weeks, then every 3 weeks, and the QLQ-C30 every 6 weeks. Prespecified key symptoms were cough, dyspnea, chest pain, appetite loss, and fatigue. Score changes from baseline to randomized treatment discontinuation were assessed using a mixed-effects model. A ≥10-point change was considered clinically relevant. Odds of improvement and time to deterioration were investigated. QLQ-C30 functioning scores were assessed post hoc. Results Questionnaire completion rates were >70% at most time points. Baseline mean scores were similar in the osimertinib and erlotinib/gefitinib arms. Scores improved in both arms, but none reached clinical relevance at 5% significance level. A statistically significant difference favoring osimertinib for chest pain was not clinically relevant (−6.84 vs −3.88; p = 0.021). Odds of improvement and time to deterioration were similar between treatments. In post hoc analyses, improvements favored osimertinib for emotional functioning (8.79 vs 4.91; p = 0.004) and social functioning (7.66 vs 1.74; p < 0.001). Cognitive functioning remained stable with osimertinib but deteriorated with erlotinib/gefitinib (0.03 vs −3.91; p = 0.005). Conclusions Key symptoms improved from baseline in both treatment arms in FLAURA. Key symptom improvements that were both statistically significant and clinically relevant were not observed in favor of either treatment arm. Clinical trial registration NCT02296125

    更新日期:2019-12-13
  • Clinical validation of a prognostic 11-gene expression profiling score in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-12
    Teresa M.S. Amaral; Marie-Christine Hoffmann; Tobias Sinnberg; Heike Niessner; Heiko Sülberg; Thomas K Eigentler; Claus Garbe

    Background Adjuvant therapies have been approved for patients with AJCC (American Joint Committee on Cancer) stage III and stage IV cutaneous melanoma (CM) after complete resection. These therapies might also be indicated for patients with high-risk stage II CM. Material and methods We included patients diagnosed with stage II melanoma between 2000 and 2016 and for which primary tumour tissue was available. The prognostic value of the 11-gene expression profiling score (GEPS) was evaluated as a dichotomized parameter (GEPS ≤0 vs. >0). Endpoints of the analysis were melanoma specific survival (MSS), distant metastasis-free survival (DMFS) and relapse-free survival (RFS). Results GEPS was determined in 245 patients ranging between −0.7 and 3.53. A total of 111 females and 134 males were included; the median follow-up was 41 months. Kaplan Meier analyses showed statistically significant survival differences between patients with high GEPS (n = 154) and low GEPS (n = 91) for MSS (p = 0.018), DMFS (p = 0.005) and RFS (p = 0.009). The 5-year and 10-year MSS was 92% in the low-GEPS and 82% and 67% in the high-GEPS group, respectively. Multivariate Cox regression analysis showed independent significance for MSS of GEPS (HR = 1.55; p = 0.006), tumor thickness (HR = 1.21; p < 0.001) and age (HR1.05; p = 0.002). Conclusion GEPS was validated as independent prognostic factor for MSS in stage II CM and could be used for therapeutic decisions when systemic therapies become available in stage II CM.

    更新日期:2019-12-13
  • A multicentric randomized phase II clinical trial evaluating high-dose thiotepa as adjuvant treatment to standard chemotherapy in patients with resectable relapsed osteosarcoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-12
    Perrine Marec-Berard; Cécile Dalban; Nathalie Gaspar; Laurence Brugieres; Jean-Claude Gentet; Cyril Lervat; Nadège Corradini; Marie-Pierre Castex; Claudine Schmitt; Hélène Pacquement; Marie-Dominique Tabone; Mehdi Brahmi; Séverine Metzger; Jean-Yves Blay; David Pérol

    Background The role of high-dose chemotherapy in relapsing osteosarcomas has not been established. We evaluated the efficacy and tolerance of high-dose thiotepa (HDTp) after standard chemotherapy (SCT) in patients with relapsed osteosarcoma. Patients and methods This randomised open-label phase II study enrolled patients 1–50 years, with local or metastatic relapse of a high-grade osteosarcoma, not progressive after two cycles of SCT, for whom a complete surgery can be achievable following treatment. The trial assigned enrolled patients in a 1:1 ratio to receive two additional courses of SCT + HDTp and autologous transplantation (Arm A), or SCT alone (Arm B). Surgery for complete resection was scheduled as soon as feasible. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS) and safety. Results From September 2009 to November 2016, 44 patients were randomised (A:22; B:22). In total, 54.5% were males, and the median age was 16 years (9-32years). The two-year OS rate was 66.7% (95% CI 42.5–82.5) (SCT + HDTp, Arm A) versus 50.0% (95% CI 28.2–68.4) for SCT alone (Arm B). Median OS was 27.4 and 24.8 months, respectively (hazard ratio [HR] 0.826, 95% CI 0.393–1.734; p = 0.6123). Median PFS was 15.6 (8.9–24.9) months in Arm A versus 7.2 (4.8–33.3) months in Arm B, p = 0.3845. Among the 22 patients treated with SCT + HDTp, 16 (72.7%) experienced at least one grade ≥3 adverse events versus 18/22 (81.8%) patients treated with SCT. No toxic death occurred. Conclusion Adjuvant HDTp failed to significantly improve OS and PFS in resectable relapsed osteosarcomas. Despite a trend of prolonged survival and an acceptable toxicity, thiotepa cannot be recommended. Key message HDTp and autologous transplantation added to SCT did not improve OS and PFS in patients with resectable relapsed osteosarcomas. Despite a trend of prolonged survival, thiotepa cannot be recommended.

    更新日期:2019-12-13
  • Impact of progression at baseline and on-treatment progression events in three large prostate cancer trials
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-11
    Debbie G. Robbrecht, Nicolas Delanoy, Ian F. Tannock, Bertrand Tombal, Mario Eisenberger, Karim Fizazi, Oliver Sartor, Florence Mercier, Stephane Oudard, Ronald de Wit

    Background There is a discussion about the optimal timing to initiate or switch treatment in metastatic castration-resistant prostate cancer (mCRPC). This post hoc analysis of 3 large trials for men with mCRPC examined the influence of the type of progression at initiation of first-line chemotherapy, as well as the type of progression during treatment, on treatment outcomes. Methods Data from the phase III studies VENICE (n = 1224), TAX327 (n = 1006) and FIRSTANA (n = 1168) were used as independent data sets. Type of progression was defined as follows: prostate-specific antigen (PSA) only (group 1), radiological (±PSA) (group 2) or pain (±PSA, ± radiological) progression (group 3). The impact of baseline type of progression on overall survival (OS) was evaluated in multivariate Cox regression analysis with backward elimination, stratified for the Eastern Cooperative Oncology Group performance score and treatment arm. Results The median OS (arms combined) from treatment initiation in VENICE was 28.6, 26.3 and 16.9 months for G1, G2 and G3, respectively (hazard ratio: 1.14 [95% confidence interval {CI}: 0.92–1.41%] in G2 and 2.13 [95% CI: 1.75–2.59%] in G3 compared with G1). Multivariate analysis (arms combined) showed that pain progression at baseline was an independent predictor of poor OS. Similar findings were observed in the TAX327 and FIRSTANA data sets. During treatment, pain or radiological progression preceded PSA progression in ~55% of the patients. The retrospective characteristic of this study is a limitation. Conclusions The type of progression at baseline strongly predicts OS in men with mCRPC treated with first-line chemotherapy. During treatment, pain and/or radiological progression preceded PSA progression as the first progression event in ~55% of the patients. This finding has the prospect to be incorporated in clinical guidelines and to be practice changing because it implies the need for regular imaging and not to rely on PSA progression alone.

    更新日期:2019-12-11
  • Treatment and outcomes in patients with central nervous system metastases from breast cancer in the real-life ESME MBC cohort
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-10
    David Pasquier, Amélie Darlix, Guillaume Louvel, Julien Fraisse, William Jacot, Etienne Brain, Adeline Petit, Marie Ange Mouret-Reynier, Anthony Goncalves, Florence Dalenc, Elise Deluche, Jean Sébastien Fresnel, Paule Augereau, Jean Marc Ferrero, Julien Geffrelot, Jean-David Fumet, Isabelle Lecouillard, Paul Cottu, Coralie Courtinard

    Aim The aims of the present study were to describe treatment patterns and survival outcomes in patients with central nervous system metastases (CNSM) selected among metastatic breast cancer (MBC) patients included in a retrospective study from the Epidemiological Strategy and Medical Economics (ESME) MBC cohort. Methods Neurological progression-free survival (NPFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Significant contributors to NPFS were determined using a multivariate Cox proportional hazards model. Results After a median follow-up of 42.8 months, of 16 701 patients included in the ESME MBC database, CNSM were diagnosed in 24.6% of patients. The most frequent treatments after diagnosis of CNSM were whole-brain radiotherapy (WBRT) (45.2%) and systemic treatment (59.3%). Median OS and NPFS were 7.9 months (95% CI: 7.2–8.4) and 5.5 months (95% CI: 5.2–5.8), respectively. In multivariate analysis, age >70 years (vs <50 years; HR = 1.40; 95% CI: 1.24–1.57), triple-negative tumours (vs HER2-/HR+; HR = 1.87; 95% CI: 1.71–2.06), HER2+/HR-tumours (vs HER2-/HR+; HR = 1.14; 95% CI: 1.02–1.27), ≥3 metastatic sites (vs < 3; HR = 1.32; 95% CI: 1.21–1.43) and ≥3 previous treatment lines (vs < 3; HR = 1.75; 95% CI: 1.56–1.96) were detrimental for NPFS. A time interval between selection and CNSM diagnosis superior to 18 months (vs <9 months; HR = 0.88; 95% CI: 0.78–0.98) was associated with longer NPFS. Conclusions This study describes current treatment patterns of MBC patients in a “real life” setting. Despite advances in stereotactic radiation therapy, most of the patients still received WBRT. More research is warranted to identify patient subsets for tailored treatment strategies.

    更新日期:2019-12-11
  • Immune checkpoint blockade for non–small cell lung cancer: What is the role in the special populations?
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-09
    R. Califano, F. Gomes, C.J. Ackermann, S. Rafee, G. Tsakonas, S. Ekman

    In recent years, non–small cell lung cancer (NSCLC) entered in a new era of anticancer treatments with the success of checkpoint inhibitors (CPIs). These are now part of daily practice from locally advanced to metastatic NSCLC. However, the registration phase III trials are highly selective and not fully representative of the patients seen in real-world clinical practice. This is particularly obvious for older and frail patients, which represent the majority of NSCLC cases worldwide. The median age of the patients enrolled in clinical trials is 10 years younger than what is seen in clinic and patients with performance status (PS) ≥2 were excluded from registration studies. No strong conclusions can be drawn from the available trials where older and frail patients have been excluded. The majority of data on efficacy according to age are derived from underpowered subgroup analysis and there are no age-specific safety data published. Current data suggest that older patients may derive a similar benefit with no increased toxicity when compared with younger patients. However, the recent development of immunotherapychemotherapy combinations and the potential higher incidence of toxicity, raise additional concerns for these populations where adequate patient selection is paramount. CPI is not recommended for patients with PS 3–4 and should be considered with caution for those with PS 2. The evidence for patients with pre-existing autoimmune disease (AID), organ transplant or chronic viral infections (such us viral hepatitis B and C or human immunodeficiency virus) is less clear and low level. Although CPI are potentially safe in selected patients with AID with minimal activity and well-controlled chronic viral infections, patients with solid organ transplant face a significant risk of graft loss and death. Therefore, a decision to treat these groups of patients should always be discussed at a multidisciplinary level.

    更新日期:2019-12-11
  • Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-09
    Li Zhang, Shanmuga Priya Bhaskaran, Teng Huang, Hui Dong, Khyati Chandratre, Xiaobing Wu, Zixin Qin, Xiaoyu Wang, Wenming Cao, Tianhui Chen, Henry Lynch, San Ming Wang

    Purpose DNA mismatch repair (MMR) genes play important roles in maintaining genome stability. Mutations in MMR genes disrupt their mismatch repair function, cause genome instability and lead to increased risk of cancer in the mutation carriers as represented by Lynch Syndrome. Studies have identified a large number of MMR variants, mostly in the Caucasian population, whereas data from non-Caucasian populations remain poorly illustrated. With the population size of 1.4 billion, knowledge of MMR variants in the Chinese population can be valuable in understanding the roles of ethnic MMR variation and cancer and to further guide clinical applications in MMR-related cancer prevention and treatment in the Chinese population. In this study, we systematically analysed the MMR variants from the Chinese population. Experimental design We performed a comprehensive MMR data mining and collected all the MMR variation data reported from 33,998 Chinese individuals consisting of 23,938 cancer and 10,060 non-cancer cases between January 1997 to May 2019. For the collected data, we performed standardisation following Human Genome Variation Society nomenclature and reannotated the MMR variant data following American College of Medical Genetics and Genomics guidelines and comparing with non-Chinese MMR data on various aspects. Results We identified a total of 540 MMR variants in the Chinese population, including 194 in MLH1, 181 in MSH2, 59 in MSH6, 53 in PMS2 single-base/indel changes and 53 large deletions/duplications in MLH1, MSH2, MSH6 and PMS2, respectively. We determined that the pathogenic/likely pathogenic carrier rate in the Chinese population was 1.6%. Comparative analysis in variant spectrum, variant types, clinical classification and founder mutations showed substantial differences of MMR variation between Chinese and non-Chinese populations and the fact that over 90% of the variants were only present in the Chinese ethnicity reveals the highly ethnic-specific nature of the Chinese MMR variation . We also developed an open-access database, dbMMR-Chinese, to host all data (https://dbMMR-chinese.fhs.um.edu.mo). The rich MMR data from a large non-Caucasian population should be valuable to study MMR variation and its relationship with cancer and provide a valuable reference resource for MMR-related cancer prevention and treatment. Conclusion Our study provides the largest MMR data set from a single non-Caucasian population and reveals that MMR variation in the humans can be highly ethnic-specific.

    更新日期:2019-12-11
  • A phase II of gemcitabine combined with pazopanib followed by pazopanib maintenance, as second-line treatment in patients with advanced leiomyosarcomas: A unicancer French Sarcoma Group study (LMS03 study)
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-10
    P. Pautier, N. Penel, I. Ray-Coquard, A. Italiano, E. Bompas, C. Delcambre, J.-O. Bay, F. Bertucci, J. Delaye, C. Chevreau, D. Cupissol, L. Bozec, J.-C. Eymard, E. Saada, N. Isambert, C. Guillemet, M. Rios, S. Piperno-Neumann, F. Duffaud

    Background Options in second-line therapy after doxorubicin-based chemotherapy for metastatic/advanced leiomyosarcoma include gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently, no combination therapy is better than monotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G + P in the second-line setting. Patients and methods Patients (pts), ECOG ≤2, with metastatic leiomyosarcomas (LMS) after first-line doxorubicin chemotherapy failure were eligible. Pts were treated with G 1000 mg/m2 on days 1 and 8 of each 21 days (maximum eight cycles), in combination with oral daily P (800 mg), until disease progression/toxicity. 9-month progression-free survival (PFS) rate was the primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in the intent-to-treat population, as 32% and 44%. Results 106 pts were included with a mean age of 59.8 years and an ECOG 0 in 63.5%; the primary tumour site was uterus in 61%. Pts were treated with P + G for a median of 3.8 mo, and P for a median of 4.2 mo. The 9-month PFS rate was 32.1% (95% CI 23.1–41.1). After a median follow-up of 14.2 months, the PFS was 6.5 months (95% CI 5.6–8.2), and the overall survival was 22.4 months (95% CI 16.9–26.5). The best response was 23.8%. The most frequent reported grade 3–4 adverse events were haematological. Conclusions LMS03 failed to show that second-line therapy, with gemcitabine combined with pazopanib, followed by pazopanib alone, was beneficial for advanced LMS patients. Eudract N°2011-001308-36 and NCT01442662.

    更新日期:2019-12-11
  • The role of chemotherapy and radiotherapy in localized extraskeletal osteosarcoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-12-02
    Marilyn Heng, Abha Gupta, Peter W. Chung, John H. Healey, Max Vaynrub, Peter S. Rose, Matthew T. Houdek, Patrick P. Lin, Andrew J. Bishop, Francis J. Hornicek, Yen-Lin Chen, Santiago Lozano-Calderon, Ginger E. Holt, Ilkyu Han, David Biau, Xiaohui Niu, Nicholas M. Bernthal, Peter C. Ferguson, John A. Abraham

    Purpose The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival. Patients and methods Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan–Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed. Results 370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%–62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26–0.80], p = 0.01). Conclusion Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.

    更新日期:2019-12-03
  • Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-29
    Nicolas Delanoy, Anne-Claire Hardy-Bessard, Eleni Efstathiou, Sylvestre Le Moulec, Umberto Basso, Alison Birtle, Alastair Thomson, Michael Krainer, Aline Guillot, Ugo De Giorgi, Ali Hasbini, Gedske Daugaard, Amit Bahl, Simon Chowdhury, Orazio Caffo, Philippe Beuzeboc, Dominique Spaeth, Jean-Christophe Eymard, Stéphane Oudard

    Aim of the study Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry. Methods The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence. Results Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes. Conclusions Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.

    更新日期:2019-11-29
  • Risk-tailored starting age of breast cancer screening based on women's reproductive profile: A nationwide cohort study
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-21
    Trasias Mukama, Mahdi Fallah, Yu Tian, Kristina Sundquist, Jan Sundquist, Hermann Brenner, Elham Kharazmi

    Background Although reproductive history is recognised to affect the risk of breast cancer, current breast cancer screening guidelines do not consider risk differences by this important factor. As there is a need for an earlier screening in women at increased risk of breast cancer, we provided evidence-based risk-adapted starting age of screening based on different reproductive profiles. Material and methods We conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931. Records of study participants in Swedish Cancer Registry, Multi-generation Register, Cause of Death Register, and national censuses (follow-up, 1958–2015) have been linked. We used 10-year cumulative risk of breast cancer curves to determine the age at which women with different reproductive factors attained the risk level at which breast screening is usually recommended. Results The 10-year cumulative risk of breast cancer at age 40, 45 and 50 years in the general population, at which current screening guidelines recommend screening was calculated. We found that women with various reproductive factors (defined by parity and age at first birth) obtained this level of risk at different ages. The difference was between nine years later and three years earlier. Conclusions This study provides the age at which women with particular reproductive profile could start risk-adapted breast cancer screening. This supplies novel information for clinicians and women about when to start breast cancer screening and is an important step towards a personalised screening.

    更新日期:2019-11-21
  • Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: Results of a phase III randomised controlled trial
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-14
    Atul Sharma, Bidhu Kalyan Mohanti, Surendra Pal Chaudhary, V. Sreenivas, Ranjit Kumar Sahoo, Nootan Kumar Shukla, Sanjay Thulkar, Sujoy Pal, Surya V. Deo, Sushmita Pathy, Nihar Ranjan Dash, Sunil Kumar, Sushma Bhatnagar, Rakesh Kumar, Seema Mishra, Peush Sahni, Venkateswaran K. Iyer, Vinod Raina

    Aim To determine equivalence of modified gemcitabine and oxaliplatin compared with gemcitabine and cisplatin in unresectable gallbladder cancer (GBC). Primary end-point was overall survival (OS). Methods Open label, prospective, randomised phase III equivalence study. Inclusion criteria included histologically proven unresectable GBC, 18 years or older, adequate organ functions and Eastern Cooperative Oncology Group ≤2. Sample size 108 patients were required in each arm to have an equivalence margin of ±2 months with power of 80%. Treatment Modified gemcitabine and oxaliplatin (mGemOx)—gemcitabine 900 mg/m2, oxaliplatin 80 mg/m2, maximum 6 cycles; gemcitabine + cisplatin (CisGem)—gemcitabine 1000 mg/m2, cisplatin 25 mg/m2, maximum 8 cycles, all day 1 and 8 every 3 weeks. Results Two hundred sixty subjects were recruited between February 2011 and July 2015. Two hundred forty-three patients (119, mGemOx and 124, CisGem) received at least 1 dose and analysed for safety and efficacy (modified intention to treat). Median OS was 8·5 months for whole group (95% confidence interval [CI]: 7·9–9·1). Median OS in mGemOx was 9 months and 8·3 months in CisGem; p = 0·057 (hazard ratio = 0·78; 95% CI = 0·60-1·02). Restricted mean OS for follow-up limited to 30 months was 11·2 months (95% CI: 9·8–12·6) in mGemOx and 10·4 months (95% CI: 9·1–11·7) in CisGem. Difference of the mean was 0·8 months with 95% CI, exceeding 2 months (−1·1 to 2·7), hence rejecting equivalence. Peripheral neuropathy, thrombocytopaenia in mGemOx and nephrotoxicity was higher with CisGem. Conclusion This trial failed to show equivalence of eight cycles of CisGem to six cycles of mGemOx. Numerically OS was better with mGemOx. Toxicities were different. The trial was not powered to answer superiority. Clinical trial registration CTRI/2010/091/001406.

    更新日期:2019-11-14
  • Health-related quality of life in patients with fully resected BRAFV600 mutation–positive melanoma receiving adjuvant vemurafenib
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-05
    Dirk Schadendorf, Anna Maria Di Giacomo, Lev Demidov, Barbara Merelli, Igor Bondarenko, Paolo A. Ascierto, Christopher Herbert, Andrzej Mackiewicz, Piotr Rutkowski, Alexander Guminski, Grant R. Goodman, Brian Simmons, Chenglin Ye, Agnes Hong, Karl Lewis

    Aim of study The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC–IIIC melanoma. Methods The phase 3 BRIM8 study (NCT01667419) randomised patients with BRAFV600 mutation–positive resected stage IIC–IIIC melanoma to 960 mg of vemurafenib twice daily or matching placebo for 52 weeks (13 × 28-day cycles). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 at baseline, cycle 1 (days 1, 15 and 22), cycle 2 (days 1 and 15), day 1 of every subsequent 4-week cycle, the end-of-treatment visit and each visit during the follow-up period. Results Completion rates for the EORTC QLQ-C30 questionnaire were high (>80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (±22.9) and 17.3 (±24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function (<10-point change from baseline at all visits) and in the symptom scores for appetite loss, fatigue and pain. As observed for the GHS/QOL score, all scores rapidly returned to baseline after completion of planned vemurafenib treatment or treatment discontinuation. Conclusions The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time.

    更新日期:2019-11-06
  • Valuing preferences for treating screen detected ductal carcinoma in situ
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-02
    Hannah L. Bromley, G. Bruce Mann, Dennis Petrie, Carolyn Nickson, Daniel Rea, Tracy E. Roberts

    Background Mammographic screening reduces breast cancer mortality but may lead to the overdiagnosis and overtreatment of low-risk breast cancers. Conservative management may reduce the potential harm of overtreatment, yet little is known about the impact upon quality of life. Objectives To quantify women's preferences for managing low-risk screen detected ductal carcinoma in situ (DCIS), including the acceptability of active monitoring as an alternative treatment. Methods Utilities (cardinal measures of quality of life) were elicited from 172 women using visual analogue scales (VASs), standard gambles, and the Euro-Qol-5D-5L questionnaire for seven health states describing treatments for low-risk DCIS. Sociodemographics and breast cancer history were examined as predictors of utility. Results Both patients and non-patients valued active monitoring more favourably on average than conventional treatment. Utilities were lowest for DCIS treated with mastectomy (VAS: 0.454) or breast conserving surgery (BCS) with adjuvant radiotherapy (VAS: 0.575). The utility of active monitoring was comparable to BCS alone but was rated more favourably as progression risk was reduced from 40% to 10%. Disutility for active monitoring was likely driven by anxiety around progression, whereas conventional management impacted other dimensions of quality of life. The heterogeneity between individual preferences could not be explained by sociodemographic variables, suggesting that the factors influencing women's preferences are complex. Conclusions Active monitoring of low-risk DCIS is likely to be an acceptable alternative for reducing the impact of overdiagnosis and overtreatment in terms of quality of life. Further research is required to determine subgroups more likely to opt for conservative management.

    更新日期:2019-11-04
  • Safety and effectiveness of regorafenib in patients with metastatic colorectal cancer in routine clinical practice in the prospective, observational CORRELATE study
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-04
    Michel Ducreux, Lone Nørgård Petersen, Leopold Öhler, Francesca Bergamo, Jean-Philippe Metges, Jan Willem de Groot, Jaw-Yuan Wang, Beatriz García Paredes, Emmanuelle Dochy, Sabine Fiala-Buskies, Andrés Cervantes, Juan Manuel O'Connor, Alfredo Falcone

    Background Regorafenib prolonged overall survival (OS) versus placebo in patients with treatment-refractory metastatic colorectal cancer (mCRC) in phase III trials. We conducted an observational study of regorafenib for patients with mCRC in real-world clinical practice. Methods The international, prospective, CORRELATE study recruited patients with mCRC previously treated with approved therapies, for whom the decision to treat with regorafenib was made by the treating physician according to the local health authority approved label. The primary objective was safety, assessed by treatment-emergent adverse events (TEAEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03). Results A total of 1037 patients were treated. The median age was 65 years (range: 24–93); 87% of patients had Eastern Cooperative Oncology Group performance status 0–1, 56% of patients had KRAS, 7% had NRAS and 4% had BRAF mutations. The initial regorafenib dose was 160 mg/day in 57% of patients. The most common grade III or IV drug-related TEAEs were fatigue (9%), hand–foot skin reaction (7%) and hypertension (6%). Drug-related grade V (fatal) TEAEs occurred in 1% of patients. Dose reductions for drug-related TEAEs occurred in 24% of patients. Median OS was 7.7 months (95% confidence interval [CI]: 7.2–8.3), and median progression-free survival (PFS) was 2.9 months (95% CI: 2.8–3.0). Conclusions In this real-world, observational study of patients with mCRC, the regorafenib toxicity profile was similar to that reported in phase III trials. The starting dose for almost half of patients was less than the approved 160-mg dose, and the median OS and PFS were in the range observed in phase III trials. Trial registration: NCT02042144.

    更新日期:2019-11-04
  • Phase II study of CC-486 (oral azacitidine) in previously treated patients with locally advanced or metastatic nasopharyngeal carcinoma
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-04
    Ricard Mesia, Paolo Bossi, Aaron R. Hansen, Ching-Yun Hsieh, Lisa F. Licitra, Eng-Huat Tan, Peng Chen, JulieAnn Miller, Lilian L. Siu, Robert I. Haddad

    Background Treatment options are limited for recurrent nasopharyngeal carcinoma (NPC). We report results from a phase II study of CC-486 (oral azacitidine) in advanced NPC. Patients and methods Patients with locally advanced or metastatic NPC and 1–2 prior treatment regimens received CC-486 300 mg daily on days 1–14 of 21-day cycles until disease progression or unacceptable toxicity. The first 6 patients of Asian-Pacific Islander (API) ethnicity received a reduced dose of 200 mg to preserve safety and tolerability; if well tolerated, subsequent API patients received CC-486 300 mg. The study could advance to stage 2 if > 4 patients achieved a response. Co-primary end-points were overall response rate (ORR) and progression-free survival (independent review). Key secondary end-points were overall survival and safety. Results Owing to faster-than-anticipated enrolment, 36 patients, including 13 of API ethnicity, were enrolled; the median age was 54.0 years. Most patients were male (81%) and had an Eastern Cooperative Oncology Group performance status ≤ 1 (97%). Among 25 efficacy-evaluable patients, the ORR was 12%; the median progression-free and overall survival were 4.7 and 18.0 months, respectively. The most common grade III/IV treatment-emergent adverse events were neutropenia (33%) and febrile neutropenia (11%). Twenty-one posttreatment deaths, primarily due to progressive disease or disease complications, and 1 on-treatment death (epistaxis, unrelated to study drug) occurred. The study did not advance to stage 2. Conclusion CC-486 did not show sufficient clinical activity to support further development as monotherapy in this patient population. The safety profile of CC-486 in NPC was consistent with that in other solid tumours.

    更新日期:2019-11-04
  • Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomised controlled trials
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-01
    Ulrich Ronellenfitsch, Katrin Jensen, Svenja Seide, Meinhard Kieser, Matthias Schwarzbach, Tracy E. Slanger, Bryan Burmeister, David Kelsen, Donna Niedzwiecki, Guillaume Piessen, Christoph Schuhmacher, Susan Urba, Cornelis van de Velde, Marc Ychou, Ralf Hofheinz, Sylvie Lorenzen

    Introduction Disease-free survival (DFS) is increasingly being used as surrogate end-point for overall survival (OS) in cancer trials. So far, there has been no validation of the surrogacy of DFS for OS for neoadjuvant treatment of gastroesophageal adenocarcinoma. Methods The study uses individual patient data (IPD) from eight randomised controlled trials (RCTs) (n = 1126 patients) comparing neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. Correlation between OS time and DFS time was calculated to evaluate individual-level surrogacy. For each trial, survival curves using the Kaplan-Meier method were plotted and hazard ratios (HRs) on the treatment effects were calculated for OS and DFS separately. Those HRs were pooled in a random-effects meta-analysis. Observed HRs were compared with predicted HRs for OS using results from an error-in-variables linear regression model accounting for the uncertainty about the estimated effect. The strength of the association was quantified by the coefficient of determination to assess trial-level surrogacy. The surrogate threshold effect was calculated to determine the minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS. Results A strong correlation between OS time and DFS time was observed, indicating a high individual-level surrogacy. For all RCTs, estimated HRs for OS and DFS were highly similar. In the meta-analysis, the overall HR for OS was virtually identical to that for DFS. The estimated coefficient of determination r2 for the association between HRs for OS and DFS was 0.912 (95% confidence interval: 0.75–1.0), indicating a very good fit of the regression model and thus a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect based on the regression analysis was 0.79. Discussion Based on strong correlations between DFS and OS, as well as a strong correlation of the treatment effects of the two end-points in the error-in-variable regression, DFS seems an appropriate surrogate marker for OS in randomised trials of neoadjuvant chemotherapy or chemoradiotherapy for gastroesophageal adenocarcinoma.

    更新日期:2019-11-01
  • The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-11-01
    B. Soldevilla, C. Carretero-Puche, G. Gomez-Lopez, F. Al-Shahrour, M.C. Riesco, B. Gil-Calderon, L. Alvarez-Vallina, P. Espinosa-Olarte, G. Gomez-Esteves, B. Rubio-Cuesta, J. Sarmentero, A. La Salvia, R. Garcia-Carbonero

    Background Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1–C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). Methods Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. Results Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. Conclusions The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.

    更新日期:2019-11-01
  • Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-10-31
    Thomas Walter, Come Lepage, Romain Coriat, Emilie Barbier, Guillaume Cadiot, Francois-Xavier Caroli-Bosc, Thomas Aparicio, Karine Bouhier-Leporrier, Olivia Hentic-Dhome, Frédérique Gay, Anne-Claire Dupont-Gossart, Muriel Duluc, Céline Lepere, Thierry Lecomte, Denis Smith, Caroline Petorin, Frédéric Di-Fiore, Francois Ghiringhelli, Thierry de Baère

    Background Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity. Methods This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7–30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%. Results Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5–43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14–23), 17 (13–22), and 51 (33–60) months. The most common grade III–IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%). Conclusions The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease. Trial registration NCT01678664 (clinicaltrials.gov).

    更新日期:2019-11-01
  • Melanoma-specific survival in patients with positive sentinel lymph nodes: Relevance of sentinel tumor burden
    Eur. J. Cancer (IF 6.680) Pub Date : 2019-10-31
    Imke Satzger, Ulrike Leiter, Nikolai Gräger, Ulrike Keim, Claus Garbe, Ralf Gutzmer

    Background The tumor burden within the sentinel lymph node (SLN) is not included in the 8th edition of the American Joint Committee of Cancer (AJCC) melanoma classification. Therefore, we analysed the prognostic relevance of the SLN tumor burden in the stage III subgroups. Patients and methods A total of 736 patients with melanoma with positive SLN and long-term follow-up (mean, 64.4 months; median, 59.0 months) were assessed. SLN tumor burden was evaluated by the maximum diameter of the largest deposit in all patients. Results By univariate Kaplan-Meier analyses, melanoma-specific survival (MSS) of patients in stage IIIA, IIIB and IIIC and lower sentinel tumor burden (cut-offs ≤0.5 mm and ≤1 mm) was significantly better than that in patients with higher sentinel tumor load (>0.5 mm and >1 mm). By multivariate analysis using the Cox model, the maximum diameter of the largest deposit (cut-off ≤0.5 mm versus >0.5 mm and cut-off ≤1 mm as continuous variables) represented an independent prognostic parameter for MSS in stage III patients. Cut-off of 0.5 mm showed a slightly higher area under the receiver operating characteristic curve (AUC = 0.617) when than the cut-off of 1 mm (AUC = 0.599). Conclusion The prognosis of patients with stage III melanoma can be determined more precisely if the SLN tumor burden is considered, also within the existing AJCC subgroups. Thus, this parameter should be included in future classifications, and our study provides benchmarks in estimating prognosis and counselling patients with melanoma with positive sentinel nodes beyond the 8th AJCC Cancer Staging Manual. The optimal cut-off remains for SLN tumor burden remains to be determined, but our results suggest that a cut-off lower than 1 mm is preferable.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Serum CEA monitoring in the follow-up of colorectal cancer patients with negative preoperative serum CEA.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-08-01
    G Mariani,M Carmellini,F Bonaguidi,M A Benelli,M G Toni

    更新日期:2019-11-01
  • Effect of Corynebacterium parvum stimulation on granulopoiesis.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-08-01
    G Eliopoulos,S André,J Meletis,J Tselentis,B Halpern

    更新日期:2019-11-01
  • Mediastinal involvement in early-stage Hodgkin's disease. Response to treatment and pattern of relapse.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-08-01
    E Velentjas,A Barrett,T J McElwain,M J Peckham

    更新日期:2019-11-01
  • Thiamin status of patients treated with drug combinations containing 5-fluorouracil.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-08-01
    M Aksoy,T K Basu,J Brient,J W Dickerson

    更新日期:2019-11-01
  • Nuclear and cytoplasmic estrogen receptors and progesterone receptors in breast cancer.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-08-01
    R Hähnel,R K Partridge,L Gavet,E Twaddle,T Ratajczak

    更新日期:2019-11-01
  • Breast cancer in Israel, 1960-1975. II. Effects of age and origin on survival.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-08-01
    Y Melnik,P E Slater,L Katz,A M Davies

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Treatment of mouse neuroblastoma with methyldopa.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-07-01
    E Chelmicka-Schorr,B G Arnason

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Estrogen binding by neoplastic human thymus cytosol.
    Eur. J. Cancer (IF 6.680) Pub Date : 1980-07-01
    F O Ranelletti,M Carmignani,P Marchetti,C Natoli,S Iacobelli

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
上海纽约大学William Glover
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug