\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{Access to early phase clinical trials for children with relapsed and
refractory neuroblastoma. A multicentre international study.}



\author[1]{Marta Cortes}%
\author[2]{Fernando Carceller}%
\author[3]{Alba Rubio-San-Simon}%
\author[4]{Sucheta Vaidya}%
\author[5]{Francisco Bautista}%
\author[6]{Lucas Moreno}%
\affil[1]{Hospital Materno Infantil }%
\affil[2]{Royal Marsden Hospital Sutton}%
\affil[3]{Hospital Universitario 12 de Octubre}%
\affil[4]{The Royal  Marsden NHS Foundation trust}%
\affil[5]{Hospital Infantil Universitario Nino Jesus}%
\affil[6]{Vall d'Hebron Hospital}%


\vspace{-1em}



  
  \date{June 10, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objectives. Neuroblastoma is the most common extracranial tumour in
children, and prognosis for refractory and relapsed disease is still
poor. Early Phase clinical trials play a pivotal role in the development
of novel drugs. Ensuring adequate recruitment is crucial. The primary
aim was to determine the rate of participation trials for children with
refractory/relapsed neuroblastoma in two of the largest Drug Development
European institutions. Methods. Data from patients diagnosed with
refractory/relapsed neuroblastoma between January 2012 and December 2018
at the two institutions were collected and analysed. Results. Overall,
48 patients were included. A total of 31 (65\%) refractory/relapsed
cases were enrolled in early Phase trials. The main reasons for not
participating in clinical trials included: not fulfilling eligibility
criteria prior to consent (12/17, 70\%) and screening failure (2/17,
12\%). Median time on trial was 4.3 months (range 0.6-13.4). Most common
cause for trial discontinuation was disease progression (67.7\%). Median
overall survival was longer in refractory (28 months, 95\% CI,
20.9-40.2) than in relapsed patients (14 months, 95\% CI, 8.1-20.1))
{[}p=0,034{]}. Conclusions. Although two thirds of children with
refractory/relapsed neuroblastoma were enrolled in early Phase trials,
recruitment rates can still be improved. The main cause for not
participating on trials was not fulfilling eligibility criteria prior to
consent, mainly due to performance status and short life expectancy.
This study highlights the hurdles to access to innovative therapies for
children with relapsed/refractory neuroblastomas and identifies key
areas of development to improve recruitment to early phase trials.%
\end{abstract}%



\sloppy


\textbf{Hosted file}

\verb`COVER LETTER.doc`  available at \url{https://authorea.com/users/428290/articles/532182-access-to-early-phase-clinical-trials-for-children-with-relapsed-and-refractory-neuroblastoma-a-multicentre-international-study}

\textbf{Hosted file}

\verb`Access to early phase clinical trials neuroblastoma LAST.docx`  available at \url{https://authorea.com/users/428290/articles/532182-access-to-early-phase-clinical-trials-for-children-with-relapsed-and-refractory-neuroblastoma-a-multicentre-international-study}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-Consort-diagram/Figure-1-Consort-diagram}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1 Baseline Patients_MC 4.0.docx`  available at \url{https://authorea.com/users/428290/articles/532182-access-to-early-phase-clinical-trials-for-children-with-relapsed-and-refractory-neuroblastoma-a-multicentre-international-study}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2OS-NBL/Figure-2OS-NBL}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

