\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[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Current Approaches to Management of Bone Sarcoma in Adolescent and Young
Adult (AYA) Patients}



\author[1]{Katrina Ingley}%
\author[2]{Alessandra Maleddu}%
\author[2]{Franel Le Grange}%
\author[3]{Craig Gerrand}%
\author[4]{Archie Bleyer}%
\author[2]{Jeremy Whelan}%
\author[2]{Sandra Strauss}%
\affil[1]{BC Children's Hospital}%
\affil[2]{University College London Hospitals NHS Foundation Trust}%
\affil[3]{Royal National Orthopaedic Hospital NHS Trust}%
\affil[4]{Oregon Health \& Science University}%


\vspace{-1em}



  
  \date{May 21, 2024}


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





\selectlanguage{english}
\begin{abstract}
Bone tumors are a group of histologically diverse diseases which occur
across all ages. Two of the commonest, osteosarcoma (OS) and Ewing
sarcoma (ES), are regarded as characteristic AYA cancers with an
incidence peak in AYAs. They are curable for some but associated with
unacceptably high rates of treatment failure and morbidity. The
introduction of effective new therapeutics for bone sarcomas is slow,
and to date, complex biology has been insufficiently characterized to
allow more rapid therapeutic exploitation. This review focuses on
current standards of care, recent advances that have or may soon change
that standard of care and challenges to the expert clinical research
community that we suggest must be met.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Primary tumors arising in bone are characterized by an almost unique age
incidence pattern, incompletely understood biology, complex and morbid
treatments and patient outcomes in need of improvement. In the
adolescent and young adult (AYA) age range, the two most common bone
sarcomas are osteosarcoma (OS) and Ewing sarcoma (ES) of bone. While a
significant proportion of young people with these diseases can be cured,
their lives are often associated with lifelong consequences, especially
in, but not limited to, physical functioning, so that survivorship
issues are an essential consideration in providing care for AYA with
bone sarcoma. Achieving improvements in survival has proved challenging
despite greater levels of international collaboration in recent decades.
This is likely multifactorial, including unequal access to expert
multidisciplinary care. Recent observations of activity of new systemic
agents against advanced disease hold hope for the future. A
well-established multi-modality treatment approach for OS and ES focuses
on systemic chemotherapy integrated with management of the primary tumor
by surgery, radiotherapy (RT) or both. The challenge for specialists is
to optimize these treatments to ensure the greatest number of young
people survive with least long-term cost.

\textbf{Epidemiology, Aetiology and Risk Factors}

Primary bone sarcomas comprise \textless{}2\% of all new malignancies in
patients of all ages. In older adolescents aged 15-19 years, however, OS
and ES account for 5.5\% of new cases of all tumor types and in 15 to 24
year-olds they comprise 3.2\% of all cancers.\textsuperscript{1,2} A
smaller proportion of chondrosarcomas, conventional type or mesenchymal,
and very rare entities such as chordoma account for the rest of bone
sarcomas in AYAs. The European age-standardized incidence rate for all
bone sarcomas across all ages/ gender per year is 1.0 per 100,000
population, \textasciitilde{}0.3 per 100,000 person-years each for OS
and ES.\textsuperscript{3} Several population-based studies provide
clear and consistent data about the relative incidence rates of these
sarcomas and particularly the relationship with age (Fig. 1A). The
commonest bone sarcomas, OS and ES, have a peak incidence in AYAs, with
a second peak in OS beyond 70 years (Fig. 1B). The male to female ratios
for OS and ES are 1.2 and 1.1.\textsuperscript{3} A racial disparity is
notable for ES, with a higher incidence in Caucasians (Fig. 1C). While
modest improvements in outcome for ES are seen in population data, due
largely from wider implementation of multidisciplinary care and
centralization, the same improvements are not apparent for OS (Fig. 1D).

OS is the most common primary bone sarcoma. In younger patients, most
frequently diagnosed between ages 10 to 19 years.\textsuperscript{4} It
arises most commonly in the extremities compared to pelvic, axial and
craniofacial primary locations in older
patients.\textsuperscript{5,6}Risk factors for OS include prior
malignancy and radiation exposure, and particularly so in older
patients,- underlying bone conditions such as Paget disease of bone and
fibrous dysplasia.\textsuperscript{7} While the majority of OS is
sporadic, inherited cancer predisposition syndromes are recognized;
these include Li- Fraumeni syndrome, hereditary retinoblastoma,
Diamond-Blackfan anemia, Rothmund-Thompson, Werner and Bloom
syndromes.\textsuperscript{8} In a recent analysis, an estimated 28\% of
OS patients of all ages were found to carry a rare germline pathogenic,
likely pathogenic variant in a cancer-susceptibility gene, with most of
those variants in autosomal dominant cancer susceptibility genes,
implicating an important role for germline genetic testing in younger
patients.\textsuperscript{9}

ES is a small round blue-cell tumor and the third most common primary
bone sarcoma of all ages, also most frequently diagnosed between ages 10
to 19 years. It arises mostly in the extremities, followed by pelvis,
ribs and vertebra and can also occur in soft tissue and viscera; 25\%
are metastatic at diagnosis.\textsuperscript{4,10} ES is characterized
by a recurrent balanced chromosomal translocation, resulting in the
fusion of the FET family gene \emph{EWSR1} with an ETS transcription
factor \emph{FLI1} in \textasciitilde{}80\%
cases.\textsuperscript{11}Variant fusions will occur between EWSR1 and
other genes, including ERG, ETV1, ETV4 and FEV.\textsuperscript{12}
Although somatic mutations in ES are rare; \emph{STAG2} and \emph{TP53}
are associated with poor outcomes.\textsuperscript{13} Well-defined
genetic or other aetiological factors are present in a small proportion
of AYAs diagnosed with ES. Germline sequencing and genealogy studies has
identified pathogenic or likely pathogenic germline mutations in
\textasciitilde{}13\% of ES patients, commonly in DNA damage repair
genes or inactivating variants associated with cancer predisposition
syndromes -such as Fanconi anemia and familial breast
cancer.\textsuperscript{14,15}

A related entity of `Ewing-like' sarcomas are a heterogeneous group of
small round cell tumors considered genetically distinct entities without
the typical ES fusions. Ewing-like sarcomas have a predilection for soft
tissues in AYAs and have other specific gene rearrangements, including
EWSR1-non ETS fusions, CIC-fused, BCOR- and NFATC2-
rearrangements.\textsuperscript{16-19} Differentiation from classical ES
suggest the need for specific investigation of optimal treatment
strategies.

\textbf{Current standard of care for AYAs}

Osteosarcoma

A multidisciplinary approach that includes multidrug chemotherapy and
surgical resection is the current standard of care for resectable OS.
About 80\% of newly diagnosed patients have resectable disease and no
radiological evidence of metastases. Historical uncontrolled trials
reported before the era of chemotherapy, indicate that surgery alone was
curative for less than 20\%, while all others would experience rapid
recurrence and death within 1-2 years.\textsuperscript{20} The use of
adjuvant chemotherapy in a randomized controlled trial between intensive
multiagent chemotherapy and surveillance, improved 2y relapse free
survival from 17\% to 66\%.\textsuperscript{21} During the last four
decades many trials were undertaken to define the most effective
regimens to be used as standard of care. Multiple strategies were
explored including different combination of agents, dose intensification
and therapy adjustments according to the chemotherapy response seen in
resection specimens.\textsuperscript{22-25}

Currently, the internationally adopted standard of care for patients
with resectable disease is a multidrug regimen including methothrexate,
doxorubicin (adriamycin) and cisplatin (MAP) administered before and
after surgical resection. In the AYA cohort there is an increased focus
in administering chemotherapy in an outpatient
setting.\textsuperscript{26} The EURAMOS-1 collaboration including over
2000 patients with operable OS receiving MAP demonstrated a 5y EFS of
54\% and overall survival \textasciitilde{}70\% for all patients,
increasing to 60\% and 76\% for localized
disease.\textsuperscript{27}Several independent risk factors, including
histologic response, age, presence of metastases, primary tumor site and
volume are associated with propensity to OS
recurrence.\textsuperscript{22,27-31} Histological response of the
primary tumor to preoperative chemotherapy has been reported as a key
prognostic factor for relapse and efforts have been made to risk
stratify for first line treatment, poor responders ([?]10\% viable tumor)
having a significantly worse 5y overall survival than good responders
(\textless{}10\% viable tumor), (45-55\% vs
75-80\%).\textsuperscript{25,27} Adding ifosfamide and etoposide to MAP
in poor responders did not significantly improve survival but increased
toxicity.\textsuperscript{25} Similarly, the addition of maintenance
pegylated interferon alfa-2b in good responders did not impact 3y
EFS.\textsuperscript{32}

Despite combined treatment, 40 to 50\% of patients experience recurrent
disease most frequently within 3 years from
diagnosis.\textsuperscript{33,34} The commonest site of recurrence is
the lungs in \textasciitilde{}80\% patients. Bone metastases are less
frequent, \textasciitilde{}15\% and local recurrence occurs in less than
10\%.\textsuperscript{34,35} Early relapse (within 24 months) is
associated with a less favorable prognosis.\textsuperscript{36}Achieving
a second complete surgical remission is crucial as some patients,
\textasciitilde{}30\% will remain disease free.\textsuperscript{34,37}
Retrospective data suggest that repeated metastasectomies may improve
survival and should be considered whenever
possible.\textsuperscript{35,37-39} However, this is dependent on
patient selection and lacks high quality prospective
evaluation.\textsuperscript{40,41}

Chemotherapy is widely used in the management of recurrent pretreated
OS, although complete and partial responses are rare and survival
benefit has not been well demonstrated in largely, retrospective
analyses.\textsuperscript{34,42,43} Outcomes depend on disease-free
interval with late relapses faring better.\textsuperscript{34} There is
no accepted standard regimen but cytotoxic agents include, ifosfamide \selectlanguage{ngerman}±
etoposide, single agent ifosfamide, gemcitabine and docetaxel,
cyclophosphamide, and carboplatin.\textsuperscript{44} Clinicians may
witness clinical benefit from the use of chemotherapy that encourages
its continued widespread use but a positive impact on quality of life
has also not been documented.

Ewing sarcoma

Current standard of care for ES has evolved over decades through
randomized trials into just-tolerated, prolonged intensive chemotherapy
regimens through the addition of cytotoxic agents, (notably-
doxorubicin, ifosfamide and etoposide) to vincristine, dactinomycin and
cyclophosphamide (VAC).\textsuperscript{45-50} Randomized trials by risk
group for newly diagnosed ES are shown in Table I. More recently, the
focus has shifted to dose-intensity of the alkylating agents and through
several large, randomized trials, a clearer international consensus has
emerged. The most recent prospective COG trial randomized patients
\textless{}50years with localized ES to receive alternating vincristine,
doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) every 3
weeks (standard) compared to every 2 weeks, facilitated by the use of
granulocyte colony stimulating factor
(intensive).\textsuperscript{51,52} 5y EFS was superior in the
intensified regimen compared with the standard arm, (73\% vs 65\%,
(\emph{P} =0.048)), with no difference in toxicity (\emph{P} =
0.056).\textsuperscript{52} The Euro Ewing 2012 trial demonstrated a
superior outcome for VDC/IE compared to the previous European standard,
VIDE/VAI in patients with localized and metastatic ES: a Bayesian
analysis demonstrated hazard ratios (HRs) of 0.70 for EFS and 0.64 for
overall survival and a 98\% posterior probability in favor of
VDC/IE.\textsuperscript{53,54} The 3-year EFS for VIDE/ VAI was 61\%
compared to 68\% for VDC/IE and there was a similar difference in
overall survival, with no excess acute toxicity with
VDC/IE.\textsuperscript{54} On the basis of these results, interval
compressed VDC/IE therapy has become the international current standard
of care for localized and metastatic ES. Dexrazoxane cardioprotection
with short infusion doxorubicin allows for safe intensification of
treatment without affecting tumor response.\textsuperscript{55} The
addition of chemotherapeutic agents to VDC/IE -such as
vincristine-cyclophosphamide-topotecan in the COG trial AEWS1031 or
irinotecan temozolomide showed no survival benefit in non-metastatic
patients.\textsuperscript{56,57}

Recurrent ES, which is mostly systemic relapse, occurs in 30-40\% of
primary localized disease and 60-80\% of metastatic
ES.\textsuperscript{58} Survival is less than 25\% overall for patients
with relapsed ES, better in later relapses \textgreater{}2y after
treatment.\textsuperscript{59,60} The management of patients with
primary refractory or recurrent ES is less well defined with several
combinations of chemotherapy in use, largely dependent on institutional
experience. An ongoing randomized multi-arm European trial (rEECur) is
recruiting relapsed ES patients between ages 4 and 50, to multiple
chemotherapy arms to determine a standard of care. Interim analyses
suggest irinotecan plus temozolomide and gemcitabine and docetaxel are
inferior to high dose ifosfamide and cyclophosphamide/ topotecan
combination.\textsuperscript{61,62} The median PFS across all cohorts
was 4.7 months with overall survival of 13.7 months across all
therapies.\textsuperscript{61}

Local management of the primary tumor in ES includes surgery or RT or a
combination of both. Complete surgical resection with clear margins (R0)
remains the most important goal for local control. 5 year local failure
rates after RT alone, surgery only, and surgery combined with RT were
15.3\%, 3.9\% and 6.6\% respectively in 956 patients treated on COG
protocols.\textsuperscript{63} The failure rate after RT alone is higher
in pelvic and extremity tumors reflecting patients with often locally
advanced tumors unsuitable for
surgery.\textsuperscript{63,64}Indications for combination treatment
include the expectation or confirmation of inadequate resection margins,
large tumors and poor response to induction
chemotherapy.\textsuperscript{65,66} Definitive RT is recommended where
surgery would result in unacceptable
morbidity.\textsuperscript{44,63,67-72} RT dose ranges from 45Gy to 66Gy
depending on anatomical location, tumor size and timing of RT in
relation to surgery.\textsuperscript{72,73} Whole lung RT may be used to
consolidate the response of lung metastases after chemotherapy and is
well tolerated although the benefit has not been unequivocally
demonstrated.\textsuperscript{74}

\textbf{Areas of clinical uncertainty for AYAs}

Osteosarcoma

\textbf{Mifamurtide} is a macrophage modulator thought to be active in
reducing the incidence of lung metastases in OS.\textsuperscript{75} Its
potential benefit has been investigated in a trial randomizing over 600
patients with localized OS to receive MAP alone or with the addition of
mifamurtide and/or ifosfamide. Although increased overall survival (from
70 to 78\% at 6y, \emph{P} =0.03) was reported for the mifamurtide arms,
the lack of significantly improved EFS and concerns about a possible
interaction between mifamurtide and ifosfamide ensured the results were
insufficient to support global approval by regulatory authorities,
restricting the use of mifamurtide to selected
countries.\textsuperscript{75-77}

\textbf{Surgical resectability} is a cornerstone of curative treatment
for OS. For some patients, especially with tumors of the pelvis, axial
skeleton and skull, complete surgical resection is not possible. There
is a lack of evidence for adjuvant or definitive RT in this situation.
RT may be used where resection is not possible or anticipated to lead to
unacceptable morbidity.\textsuperscript{44,78-80} Doses of 60Gy or
higher, and ideally 70Gy are
indicated.\textsuperscript{78,81-83}Strategies to improve outcomes,
including comprehensive evaluation of particle beam therapy in this
setting, are a priority. The role of\textbf{adjuvant chemotherapy in
patients undergoing complete surgical resection of relapsed disease} ,
either local or distant, remains unclear.\textsuperscript{34-37,42}

\textbf{Identification of metastatic disease} at diagnosis is essential
for prognosis and management. Although only 20\% of patients have
clinically evident metastases at onset, sensitivity of cross sectional
imaging demonstrates 30-45\% have pulmonary nodules of uncertain
clinical significance that do not meet defined COG criteria for
metastases and about one third of these progress to metastatic
disease.\textsuperscript{84-86} Surgical sampling is undertaken in some
centers but its value in determining overall survival and guiding
treatment is unproven.\textsuperscript{85,87} Data to support the use of
FDG-PET/CT scanning both for accurate staging, especially of the
skeleton, and to determine response to chemotherapy, supports its use in
selected patients.\textsuperscript{88-90}

Approaches to \textbf{follow-up after treatment} vary in visit
intervals, pulmonary imaging modalities and monitoring for late effects
of treatment. Access to rehabilitation, assistance in resuming progress
on achieving life skills and identifying psychological impacts are all
vital parts of effective follow up for AYAs but there is considerable
variation in recommendations and practice, indicating a need for
collaborative prospective evaluation and
evidence-seeking.\textsuperscript{91-94}

Ewing sarcoma

\textbf{Risk stratification for} ES lacks consistency and a unified
consensus for stratifying localized disease may enable reliable
interpretation of international trials. European collaborative groups
have used primary site, tumor volume, metastases and histologic response
to stratify consolidation treatment, whereas the presence of metastatic
disease alone is used in North America. Histologic response varies
depending on the number and type of treatment cycles prior to local
therapy and with a recent move towards pre surgical RT may no longer be
as relevant.

\textbf{Staging of ES} has conventionally included a bone marrow biopsy.
With the advent and familiarity of functional imaging in solid tumors,
excellent correlation rates have been demonstrated between bone marrow
biopsy and FDG-PET/CT in patients with ES.\textsuperscript{95-99} WB-MRI
appears comparable to FDG-PET/CT and superior to bone scintigraphy,
without requiring ionising radiation.\textsuperscript{88,100} In centers
with access to these imaging modalities, it is possible to avoid an
invasive bone marrow biopsy. Widespread acceptance for PET-CT or
alternatively, WB-MRI as the standard for staging bone marrow will
require prospective trials that incorporate large homogenous cohorts of
patients with ES.

The role of \textbf{high dose (HD) chemotherapy} in ES remains
controversial due to an overreliance on uncontrolled
data.\textsuperscript{101-104} A randomized trial demonstrated
consolidative HD chemotherapy using busulphan and melphalan (BuMel)
confers a survival benefit in localized high-risk ES (large primary
tumor, \textgreater{}200mls or poor response to induction VIDE
chemotherapy) compared to standardized VIDE/VAI chemotherapy, with 3y
EFS and overall survival of 69\% vs. 56.7\%(\emph{P} =0.026), and 78\%
vs. 72.2\% ( \emph{P} =0.028) respectively.\textsuperscript{105} No
benefit from BuMel, compared with conventional VAI with whole lung
irradiation, was seen in patients with pulmonary
metastases.\textsuperscript{106} Additional treosulfan and melphalan HD
chemotherapy over standard VIDE induction/ VAC consolidation
demonstrated no benefit in patients \textgreater{}14 years with primary
metastatic ES.\textsuperscript{107} No randomized studies have been
conducted in patients with recurrent or progressive disease in whom
observational data indicates a potential greater benefit than seen in
first line treatment.\textsuperscript{102,108}

Debate often centers on choice of modality, sequence and timing
for\textbf{local control management} . Combined modality treatment,
favored in Europe, has resulted in excellent local control
rates.\textsuperscript{66} There has been a move towards delivering RT
pre-operatively aiming to reduce the impact of surgical fixation on the
quality of RT and reducing the risk of late effects with lower doses,
but at the risk of increasing wound complications which in turn
compromise complex bone reconstructions.\textsuperscript{109} Complete
resection of chest wall tumors appear superior to treatment with RT in
improving survival.\textsuperscript{110} Sacral tumors demonstrate
improved survival with definitive RT, compared to non-sacral pelvic
tumors that do better with combined surgery and
RT.\textsuperscript{64}The role of surgery for patients with spinal ES
has to be considered carefully. Spinal decompressive surgery (usually in
an emergency setting) is usually intralesional increasing the risk of
local recurrence whereas definitive RT is associated with better
outcomes.\textsuperscript{111} Best practice is to tailor treatment for
each patient individually with input from an expert multidisciplinary
sarcoma panel.

\textbf{New radiation techniques}

The potential for RT to increase the late effects of treatment is
particularly important in AYAs in whom ES is treated with curative
intent. Modern RT techniques, image guided RT, intensity modulated
photon radiotherapy (IMRT) and particle beam therapy such as proton beam
therapy (PBT), deliver improved conformal RT to the target while
reducing the volume of normal tissue that receive damaging doses of RT.
As a result of the physical characteristics of PBT, significantly less
whole-body dose is delivered compared to IMRT, reducing low as well as
high doses outside the target (Fig. 2). This may reduce late effects of
RT as well as the risk of radiation-induced malignancies and this
dosimetric benefit has been sufficient to introduce PBT as the
preferential radiation modality in the treatment of many pediatric and
AYA cancers.\textsuperscript{112-115} Data on outcomes for these
techniques in ES is limited but PBT was well tolerated by a small series
of children with ES with a low incidence of significant
toxicity.\textsuperscript{116}

The risk of ovarian dysfunction from pelvic RT pelvis increases with
radiation dose. \textsuperscript{117-119} PBT avoids significant dose to
at least one of the ovaries potentially reducing the risk of infertility
and premature menopause.\textsuperscript{151} Surgical transposition or
translocation may be used to move one or both ovaries away from the RT
target if indicated.\textsuperscript{120}

Modern RT techniques also facilitate dose escalation, both in ES at
challenging sites (head and neck, pelvis and spine) and in the more
radioresistant OS that require high RT doses.\textsuperscript{83,121}PBT
to treat OS, alone or in combination with photons to a mean dose of
68.4Gy, resulted in a 5 year LC rate of
72\%.\textsuperscript{81}Internal fixation with carbon fibre and PEEK,
particularly along the spinal axis, is encouraged to improve the
homogeneity and reliable delivery of RT at these
sites.\textsuperscript{122}

\textbf{New surgical techniques}

The decades since widespread adoption of limb-sparing surgery for
primary bone tumors have seen incremental improvements in the ability of
surgeons to remove tumors whilst maintaining as much function as
possible in the affected limb. In any procedure, surgeons and patients
must balance the oncological benefits of wider resections with the
morbidity of removing normal tissues, such as muscle, bone and nerves.

To achieve this, surgeons have to define the anatomic location and
extent of tumor to enable accurate complete resection. MRI remains the
gold standard to identify the intramedullary extent of primary bone
tumors, including skip metastases.\textsuperscript{100,123} Preoperative
imaging however, is unfortunately not able to assess the response of
tumors to neoadjuvant chemotherapy with sufficient reliability to
influence surgical options.\textsuperscript{124} Intraoperative imaging
techniques, such as fluorescence using indocyanine green, offer the
prospect of guiding surgeons towards improved surgical margins, but have
yet to be proven in large scale clinical
trials.\textsuperscript{125}Novel techniques including intraoperative
navigation and personalized custom jigs to guide bone resections, are
becoming more established, may increase safety, and when matched with
implants using additive layer manufacturing and porous ingrowth
surfaces, offer the ability to improve margins whilst preserving normal
tissue, (Fig. 3).\textsuperscript{126}

For some patients with large tumors where it may not be possible to
preserve the limb, or when the expected functional differences between
limb-sparing surgery and amputation are small and the risks of
limb-sparing surgery high, amputation remains the best option.
Reconstruction with the uninvolved part of the limb, for example, by
rotationplasty or tibial turn-up may be helpful, particularly in
children.\textsuperscript{127} Advances in prosthetics and other
technologies including transosseous fixation devices offer the potential
for improved function for some amputees.\textsuperscript{128}

Limb preservation carries a risk of local recurrence. In OS,
retrospective studies have evaluated the risk in terms of the surgical
margins, chemotherapy response and proximity to major
vessels,\textsuperscript{129,130} but the application of these systems
in prospective decision making has yet to be established.

Growth and the long-term complications of surgical reconstructions are
further issues for adolescents. Growing endoprostheses contain a
mechanism which is activated in outpatients using a magnetic coil.
Although these implants have reduced the number of operations required
after endoprosthetic reconstruction, patients do not escape further
surgery, but the rate of limb preservation remains high. Bone-compatible
collars encourage bone growth onto the surface of implants and reduce
the risk of aseptic loosening when successful integration occurs. New
porous designs may have some advantages but these remain to be
proven.\textsuperscript{131} Antibacterial silver surface treatments
have also become widely adopted with the aim of reducing the risk of
deep infection. However, studies of their efficacy are retrospective and
they have not been subjected to a prospective randomized trial
.\textsuperscript{132}

\textbf{Emerging targeted therapeutics}

Targeted therapies are under investigation for recurrent ES and OS but
are not standard of care at this time. Trial accrual for AYAs has
traditionally been poor, especially in the 20-29y age group and
correlates with modest gains in survival.\textsuperscript{133} Greater
efforts are unfolding internationally to increase access to specialist
centers and clinical trials, particularly of novel agents with age
inclusion criteria across the AYA spectrum,\textsuperscript{134} and
supported by multi-stakeholder platforms such as
ACCELERATE\textsuperscript{135} to include adolescents
\textgreater{}12yo, as evidenced by the novel agent trials in Table II.

\textbf{Multitargeted tyrosine kinase small molecule
inhibitors}investigated in OS and ES demonstrate single agent activity.
Antiangiogenic TKIs, often multitargeted to various receptors such as
VEGFR are accessible through phase 1 and 2 clinical trials for AYAs with
relapsed or refractory ES and OS. They have been used either as a single
agent or in combination with sarcoma responsive chemotherapy:
regorafenib,\textsuperscript{136-139}
carbozatinib,\textsuperscript{140}apatinib,\textsuperscript{141}
lenvatinib,\textsuperscript{142}(summarized in Table II). Lenvatinib has
been demonstrated to be tolerated in combination with ifosfamide and
etoposide in patients with relapsed OS and is the subject of an ongoing
randomized phase II trial.\textsuperscript{142} The challenge is how
best to investigate these agents in the adjuvant setting and integrate
them into intensive combination therapy regimens.

\textbf{Poly-ADP-ribose polymerase 1 (PARP1) inhibitors} are under
clinical evaluation in ES, based on promising preclinical activity and
evidence that PARP1 inhibitors induced DNA damage in tumors deficient in
DNA repair mechanisms.\textsuperscript{143} Olaparib trialled as a
single agent in a prospective phase II trial was disappointing with no
objective responses in heavily pre-treated
ES,\textsuperscript{144}however potentiation of activity in combination
with chemotherapeutic agents, especially temozolomide and or irinotecan
in preclinical studies led to combination clinical trials of talazoparib
and niraparib.\textsuperscript{145-147} These demonstrated varied
efficacy in pediatric and AYA patients with refractory/ recurrent ES
with toxicity limiting dose intensity, Table II. Additional trials are
ongoing. Pre-clinical programmes are currently evaluating PARP
inhibition as a therapeutic target in OS based on potential evidence of
a ``BRCAness'' phenotype that may lead to increased sensitivity to these
agents, although validation using patient-derived models is required
before embarking on clinical trials.\textsuperscript{148-150}

The \textbf{role for immunotherapy} in ES and OS is currently limited
with little evidence of efficacy in initial trials of checkpoint
inhibition, particularly for ES which has a low mutation burden. Further
work and trials are ongoing to determine biomarkers to identify subsets
of patients or combination therapy that may be of more
benefit.\textsuperscript{151-154} Disialogangliosides, GD2 is a
potential cell surface target expressed by ES and
OS.\textsuperscript{155,156} Current phase 1 clinical trials
investigating anti-GD2 monoclonal antibodies with immunoadjuvants are
recruiting AYAs with relapsed solid tumors including ES and OS,
(NCT00743496 at https://ClinicalTrials.gov/). There is support for the
utility of dinutuximab in combination with irinotecan and temozolomide
in neuroblastoma,\textsuperscript{157} cytotoxic agents also used in
bone sarcoma and we await results of early phase clinical trials
evaluating anti-GD2-CART cells in OS, (NCT02107963 at
https://ClinicalTrials.gov/).

\textbf{Targeting the FET-ETS translocation} is challenging as the
EWSR1-FLI fusion protein lacks enzymatic activity and binding sites for
small molecules.\textsuperscript{16} TK-216, a clinical derivative of
YK-4-279 is a novel small molecule that inhibits EWS-FLI1 transcription
by blocking co-immunoprecipitation with RNA helicase
A;\textsuperscript{158} this is under evaluation in a phase 1 clinical
trial in combination with vincristine based on synergistic anti-tumor
activity demonstrated by YK-4-279.\textsuperscript{159} Very early
interim trial analyses (NCT02657005, https://ClinicalTrials.gov/) report
two pronounced clinical responses for more than 24 and 18 months
following treatment with TK216 in relapsed/ refractory
ES.\textsuperscript{160}

\textbf{Conclusion}

Despite progress made in pathology, imaging and local control modalities
coordinated by specialist sarcoma multidisciplinary centers, AYA
patients with primary bone sarcomas continue to experience inferior
outcomes. The reasons are multifactorial, including aggressive complex
biology that remains ill-understood as well as reduced access to novel
therapeutics and clinical trials along with unique psychosocial issues.
There is now international consensus supporting standardized first line
treatment for ES and OS. With evolving modern day imaging techniques
(WB-MRI, FDG-PET/CT) and new RT and surgical approaches, local treatment
should be tailored to the patient and multidisciplinary collaboration is
crucial. New therapeutic agents show promise for AYA sarcomas. The
challenge is to explore what value these agents may bring to first-line
therapy and how they can be best delivered alongside standard of care
treatments. Their inclusion into large randomized phase 3 international
trials, along with the validation of biomarkers that signal refractory
disease and can reliably predict response is required to fully evaluate
their potential.

\textbf{Conflict of Interest}

The authors do not have any conflicts of interest to declare.

\textbf{Acknowledgements}

SJS is funded in part by UCLH NIHR Biomedical Research Centre.

\textbf{Funding disclosure}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.



\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Figure 1. The incidence and outcomes of primary bone sarcoma
using Surveillance, Epidemiology, and End Results (SEER) data.}

\textbf{A-C.} The incidence trends of bone sarcoma, SEER 21, overall
from 2000 to 2017- histological type, gender and ethnicity by age of
diagnosis. Data from SEER.\textsuperscript{2} \textbf{D.} Five-year
relative survival rates for osteosarcoma and Ewing sarcoma, SEER9, from
patients diagnosed between 1975 to 2012 with at least 5-years follow-up
for survival analyses. Data from SEER.\textsuperscript{161,162}



\textbf{TABLE I. Randomized trials by risk group for newly diagnosed
Ewing sarcoma.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Ref.\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Trial\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Population\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Pts \emph{(n)}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Treatment\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Survival outcomes\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Standard risk, localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Standard risk, localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Standard risk, localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Standard risk, localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Standard risk, localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Standard risk, localized\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Paulussen\textsuperscript{49}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
EICESS-92\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Localized, Tumor volume \textless{}100ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
155\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Induction (VAIA x4) + Randomization: VAIA x10 vs. VACA x10
(cyclophosphamide vs ifosfamide)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
3y EFS 74\% vs. 73\%, HRs for EFS and overall survival 0.91 VAIA vs.
VACA\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Le Deley\textsuperscript{50}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Euro-Ewing99 R1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}50yo Localized, either good histologic response
(\textgreater{}90\%) or Tumor volume (\textless{}200ml)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
856\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Induction (VIDE x6, VAI x1) Randomization: VAIx7 vs. VACx7\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
3y EFS and overall survival for VAI vs. VAC, 78.2\% vs. 75.4\% and
85.5\% vs. 85.9\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Localized\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Localized\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Grier\textsuperscript{48}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
INT-0091 (CCG-7881 and POG-8850)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}30yo\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
398\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Standard (VACA) vs experimental (VACA + IE)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5yr EFS and overall survival for standard vs. experimental, 54\% vs.
69\% (\emph{p} 0.005) and 61\% vs. 72\% (\emph{p} 0.01)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Granowetter\textsuperscript{163}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
INT-0154\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}30yo Localized, bone + soft tissue\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
478\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VDC/IE (17 cycles, 48 weeks) vs. dose intensified VDC/IE (11 cycles, 30
weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
5y EFS and overall survival for standard vs. dose intensified, 72.1\%
vs. 70.1\% and 80.5\% vs. 77\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Womer\textsuperscript{52}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
COG AEWS0031\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}50yr age Localized\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
568\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Randomization: VDC/IE standard (q3/52) vs. VDC/IE intensified
(q2/52)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
3y EFS and overall survival for std vs. intensified, 65\% vs. 73\%
(\emph{p} 0.048) and 77\% vs. 83\% (\emph{p} 0.056) Similar
toxicity\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
High risk, localized*\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
High risk, localized*\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
High risk, localized*\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
High risk, localized*\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
High risk, localized*\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
High risk, localized*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Whelan\textsuperscript{105}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Euro-Ewing99/ Ewing-2008\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}50yo Poor histologic response ([?]90\%), Tumor volume
[?]200ml\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
240\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Induction (VIDEx6, VAIx1) Randomization: VAI vs. Bu-Mel/ ASCT\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
8y EFS and overall survival for VAI vs. Bu-Mel, 47.1\% vs. 60.7\%
(\emph{P} 0.026) and 55.6\% vs. 64.5\% (\emph{p} 0.028)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Metastatic (lungs only)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Metastatic (lungs only)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Metastatic (lungs only)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Metastatic (lungs only)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Metastatic (lungs only)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Metastatic (lungs only)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Dirksen\textsuperscript{106}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Euro-Ewing99 R2Pulm/ EWING-2008\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}50yo Pulmonary/pleural metastases, nil other\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
287\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VAI + WLI vs. Bu-Mel\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
3y EFS 50.6\% vs. 56.6\%, HR= 0.79, \emph{p}=0.16 3yr OS 68\% vs.
68.2\%, HR=1.00, \emph{p}=0.99\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multisite-metastatic (other)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multisite-metastatic (other)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multisite-metastatic (other)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multisite-metastatic (other)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multisite-metastatic (other)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multisite-metastatic (other)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Paulussen\textsuperscript{49}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
EICESS-92\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Volume [?]100ml or \selectlanguage{ngerman}±Metastases (any)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
492\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VAIA x14 vs. EVAIA x4 + EVAIAx10 (addition of etoposide)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
3y EFS 47\% vs. 52\% (\emph{p}=0.47)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Brennan\textsuperscript{54}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Euro-Ewing-2012\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textless{}50yo Localized +/- Metastases (lung or other)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
640\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
VIDE/ VAI vs. VDC/ IE\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
HRs 0.70 for EFS, 0.64 for overall survival in favor of VDC/ IE\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Definitions.}

\textbf{*} High risk localized defined as a tumor volume
\textgreater{}200mls, poor response to neoadjuvant chemotherapy with
\textless{}90\% necrosis.

Chemo combinations- VAC: vincristine, dactinomycin, cyclophosphamide;
VAI: vincristine, dactinomycin, ifosfamide; IE: ifosfamide, etoposide;
VACA: vincristine, dactinomycin, cyclophosphamide, doxorubicin; VAIA:
vincristine, dactinomycin, ifosfamide, doxorubicin; EVAIA: plus
etoposide; VIDE: vincristine, ifosfamide, doxorubicin, etoposide.

Bu-Mel/ ASCT: Busulphan Melphalan conditioning with autologous stem cell
transplant.

WLI: whole lung irradiation.

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Figure 2. Example PBT plans for pelvic and sacral tumors in
AYAs.\textsuperscript{164}}

Axial and coronal images of two definitive PBT plans to treat locally
advanced pelvic ES. An iliac bone primary in a 16-year-old female
(\textbf{A-B} ) and sacral tumor in a 19-year-old female (\textbf{C-D}
). Red colour wash represents high dose, green moderate and blue the low
dose.

\textbf{Hosted file}

\verb`image3.emf`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Figure 3. Surgical techniques for primary bone sarcoma.}

\textbf{A} . Complex navigation plan showing proposed resection planes
for low grade osteosarcoma of the iliac wing. \textbf{B} .
Reconstruction of the hip after navigated extraarticular resection using
modular porous acetabular reconstruction system. \textbf{C} . 3D printed
custom jig for resection of femoral diaphyseal Ewing sarcoma before
insertion of custom implant.



\textbf{TABLE II. Trials investigating new therapeutics for advanced or
metastatic ES and OS.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Clinical trial\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Drugs\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Patient group\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Outcome measures\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Common / significant grade 3 or 4 toxicity (\textgreater{}10\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multi-targeted TKIs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multi-targeted TKIs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multi-targeted TKIs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multi-targeted TKIs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multi-targeted TKIs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Multi-targeted TKIs\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Italiano \emph{et al}, 2020.\textsuperscript{140}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CABONE-multicenter, single arm, phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cabozantinib\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Advanced ES (n=39) and OS (n=42), [?]12yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ORR 26\% in ES, median PFS 4.4 mo, ORR 12\% in OS with 33\% PFS at 6
mo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hypophosphataemia, raised AST, palmar-plantar syndrome, pneumothorax,
neutropenia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Duffaud \emph{et al}, 2019.\textsuperscript{137}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
REGOBONE- double blind, placebo-controlled, phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Regorafenib\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Progressive pretreated OS, n=43, [?]10yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Median PFS 16.4w (regorafenib) vs 4.1w (placebo)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hypertension, hand-foot skin reaction, fatigue, hypophosphataemia, chest
pain\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Duffaud \emph{et al}, 2020.\textsuperscript{139}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
REGOBONE- double blind, placebo-controlled, phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Regorafenib\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Metastatic relapsed pretreated ES, n=41, [?]10yo\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
ORR 22\% (5/23), median PFS- 11.4w (regorafenib) vs 3.9w (placebo)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Diarrhoea, hand-foot skin reaction\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Davis \emph{et al}, 2019.\textsuperscript{136}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
SARC024- randomized, double blind, phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Regorafenib\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Advanced/ metastatic pretreated OS, n=42, 18-76yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Median PFS- 3.6mo and 1.7mo with regorafenib vs placebo,
\emph{P}.017\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hypertension\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Xie \emph{et al}, 2019.\textsuperscript{141}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Single arm, phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Apatinib\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Relapsed/ unresectable OS, n=37, [?]16yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ORR 43\%, 4mo PFS 57\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Pneumothorax, wound dehiscence\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Gaspar \emph{et al}.\textsuperscript{165}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Single arm, phase 1/2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Lenvatinib single agent\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Relapsed OS, n=31, 2 to [?]25yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ORR 6.9\%, 4mo PFS 32\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Headache, diarrhoea, vomiting, decreased appetite, proteinuria,
hypothyroidism, hypertension, pyrexia, weight loss\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Gaspar \emph{et al}.\textsuperscript{142}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Single arm, phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Lenvatinib + etoposide + ifosfamide in phase 2 expansion cohort\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Relapsed/ refractory OS, n=22 (8 evaluable patients in phase 2), 2 to
[?]25yo\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Phase 1 dose finding cohort: ORR 12.5\%, 4mo PFS in 12/18 (68\%) Phase 2
cohort: 4mo PFS in 5/8 (62\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Pneumothorax, haematologic toxicity\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PARP inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PARP inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PARP inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PARP inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PARP inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
PARP inhibitors\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Choy \emph{et al}, 2014.\textsuperscript{144}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Single arm, prospective phase 2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Olaparib\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Metastatic/ recurrent ES, n=12, 18-70yo\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Median PFS 5.7w, SD in 4/12\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Haematologic, pain\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Chugh \emph{et al}, 2020.\textsuperscript{146}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SARC025- multicenter, phase 1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Niraparib + temozolomide (Arm 1) or irinotecan (Arm 2)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Advanced ES, n=29, [?]13yo\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Median PFS in Arm 1: 9w and in Arm 2: 16w Arm 1: ORR 0/17 Arm 2: ORR
8\%- 1/12 PR and 6 SD\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Arm 1- DLT: Haematologic, Arm 2- DLT: gastrointestinal toxicity,
elevated ALT\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Schafer \emph{et} \emph{al}, 2019.\textsuperscript{145}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Single arm, phase 1/2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Talazoparib plus temozolomide\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Recurrent/ refractory solid tumors, n=40, 4-25yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ES- 2/10 prolonged SD (8 cycles)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
DLTs: haematologic\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Federico \emph{et al}, 2020.\textsuperscript{166}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Single arm, phase 1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Talazoparib + irinotecan (A) plus temozolomide (B)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Recurrent/ refractory solid tumors (50\% ES), n=41, median age
14.6yo\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ORR 10\% (A), ORR 25\% (B)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Febrile neutropenia, diarrhoea\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
EWSR1-FLI1 target agents\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
EWSR1-FLI1 target agents\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
EWSR1-FLI1 target agents\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
EWSR1-FLI1 target agents\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
EWSR1-FLI1 target agents\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
EWSR1-FLI1 target agents\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Ludwig \emph{et al}, 2021.\textsuperscript{160}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
TK216-01, phase 2 dose (RP2D)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
TK216\selectlanguage{ngerman}± vincristine\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Relapsed/ refractory metastatic ES, mean age 31yo A. Schedule escalation
cohort, n=32 B. 14-day infusion 200mg/m\textsuperscript{2}/d (RP2D)
expansion cohort, n=35\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CR 7\%, SD 39\%, PD 54\%, SD median duration 113 days (B) 3 patient
tumor responses\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Most common: haematologic toxicity, fatigue.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Definitions.} ORR: objective response rate; PFS: progression
free survival; w: weeks; mo: months; CR: complete response, PR: partial
response; SD: stable disease; PD: progressive disease; DLT: dose
limiting toxicity.



\textbf{References}

1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2020. CA Cancer J
Clin 70:7-30, 2020

2. Surveillance, Epidemiology, and End Results (SEER) Program
(www.seer.cancer.gov) SEER*Stat Database: Incidence- SEER Research
Limited-Field DATA, 21 Registries, Nov 2020 Sub (2000-2018)- Linked to
County Attributes- Time Dependent (1990-2018)- Income/ Rurality,
1969-2019 Counties, National Cancer Institute, DCCPS, Surveillance
Research Program, released April 2021, based on the November 2020
submission.,

3. Amadeo B, Penel N, Coindre JM, et al: Incidence and time trends of
sarcoma (2000-2013): results from the French network of cancer
registries (FRANCIM). BMC Cancer 20:190, 2020

4. Gatta G, Capocaccia R, Botta L, et al: Burden and centralised
treatment in Europe of rare tumours: results of RARECAREnet-a
population-based study. Lancet Oncol 18:1022-1039, 2017

5. Whelan J, McTiernan A, Cooper N, et al: Incidence and survival of
malignant bone sarcomas in England 1979-2007. Int J Cancer 131:E508-517,
2012

6. de Pinieux G, Karanian M, Le Loarer F, et al: Nationwide incidence of
sarcomas and connective tissue tumors of intermediate malignancy over
four years using an expert pathology review network. PLoS One
16:e0246958, 2021

7. Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and
survival rates from 1973 to 2004: data from the Surveillance,
Epidemiology, and End Results Program. Cancer 115:1531-1543, 2009

8. Hameed M, Mandelker D: Tumor Syndromes Predisposing to Osteosarcoma.
Adv Anat Pathol 25:217-222, 2018

9. Mirabello L, Zhu B, Koster R, et al: Frequency of Pathogenic Germline
Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.
JAMA Oncol 6:724-734, 2020

10. Jawad MU, Cheung MC, Min ES, et al: Ewing sarcoma demonstrates
racial disparities in incidence-related and sex-related differences in
outcome: an analysis of 1631 cases from the SEER database, 1973-2005.
Cancer 115:3526-3536, 2009

11. Turc-Carel C, Aurias A, Mugneret F, et al: Chromosomes in Ewing's
sarcoma. I. An evaluation of 85 cases of remarkable consistency of
t(11;22)(q24;q12). Cancer Genet Cytogenet 32:229-238, 1988

12. Sorensen PH, Lessnick SL, Lopez-Terrada D, et al: A second Ewing's
sarcoma translocation, t(21;22), fuses the EWS gene to another
ETS-family transcription factor, ERG. Nat Genet 6:146-151, 1994

13. Tirode F, Surdez D, Ma X, et al: Genomic landscape of Ewing sarcoma
defines an aggressive subtype with co-association of STAG2 and TP53
mutations. Cancer Discov 4:1342-1353, 2014

14. Brohl AS, Patidar R, Turner CE, et al: Frequent inactivating
germline mutations in DNA repair genes in patients with Ewing sarcoma.
Genet Med 19:955-958, 2017

15. Abbott D, O'Brien S, Farnham JM, et al: Increased risk for other
cancers in individuals with Ewing sarcoma and their relatives. Cancer
Med 8:7924-7930, 2019

16. Grunewald TGP, Cidre-Aranaz F, Surdez D, et al: Ewing sarcoma. Nat
Rev Dis Primers 4:5, 2018

17. Miettinen M, Felisiak-Golabek A, Luina Contreras A, et al: New
fusion sarcomas: histopathology and clinical significance of selected
entities. Hum Pathol 86:57-65, 2019

18. Antonescu CR, Owosho AA, Zhang L, et al: Sarcomas With
CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive
Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg
Pathol 41:941-949, 2017

19. Cohen-Gogo S, Cellier C, Coindre JM, et al: Ewing-like sarcomas with
BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological
retrospective study from the Societe Francaise des Cancers de L'Enfant.
Pediatr Blood Cancer 61:2191-2198, 2014

20. Dahlin DC, Coventry MB: Osteogenic sarcoma. A study of six hundred
cases. J Bone Joint Surg Am 49:101-110, 1967

21. Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant
chemotherapy on relapse-free survival in patients with osteosarcoma of
the extremity. N Engl J Med 314:1600-1606, 1986

22. Souhami RL, Craft AW, Van der Eijken JW, et al: Randomised trial of
two regimens of chemotherapy in operable osteosarcoma: a study of the
European Osteosarcoma Intergroup. Lancet 350:911-917, 1997

23. Bramwell VH, Burgers M, Sneath R, et al: A comparison of two short
intensive adjuvant chemotherapy regimens in operable osteosarcoma of
limbs in children and young adults: the first study of the European
Osteosarcoma Intergroup. J Clin Oncol 10:1579-1591, 1992

24. Lewis IJ, Nooij MA, Whelan J, et al: Improvement in histologic
response but not survival in osteosarcoma patients treated with
intensified chemotherapy: a randomized phase III trial of the European
Osteosarcoma Intergroup. J Natl Cancer Inst 99:112-128, 2007

25. Marina NM, Smeland S, Bielack SS, et al: Comparison of MAPIE versus
MAP in patients with a poor response to preoperative chemotherapy for
newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label,
international, randomised controlled trial. Lancet Oncol 17:1396-1408,
2016

26. Anderson PW, P.; Lazarte, T.; Gore, L.; Salvador, L. \&
Salazar-Abshire, M.: Outpatient chemotherapy, family-centered care,
electronic information, and education in adolescenets and young adults
with osteosarcoma. Clinical Oncology in Adolescents and Young Adults.
3:1-11, 2013

27. Smeland S, Bielack SS, Whelan J, et al: Survival and prognosis with
osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1
(European and American Osteosarcoma Study) cohort. Eur J Cancer
109:36-50, 2019

28. Jeys LM, Grimer RJ, Carter SR, et al: Post operative infection and
increased survival in osteosarcoma patients: are they associated? Ann
Surg Oncol 14:2887-2895, 2007

29. Kim MS, Lee SY, Lee TR, et al: Prognostic nomogram for predicting
the 5-year probability of developing metastasis after neo-adjuvant
chemotherapy and definitive surgery for AJCC stage II extremity
osteosarcoma. Ann Oncol 20:955-960, 2009

30. Song WS, Jeon DG, Kong CB, et al: Tumor volume increase during
preoperative chemotherapy as a novel predictor of local recurrence in
extremity osteosarcoma. Ann Surg Oncol 18:1710-1716, 2011

31. Moore C, Eslin D, Levy A, et al: Prognostic significance of early
lymphocyte recovery in pediatric osteosarcoma. Pediatr Blood Cancer
55:1096-1102, 2010

32. Bielack SS, Smeland S, Whelan JS, et al: Methotrexate, Doxorubicin,
and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus
MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good
Histologic Response to Preoperative MAP: First Results of the EURAMOS-1
Good Response Randomized Controlled Trial. J Clin Oncol 33:2279-2287,
2015

33. Duffaud F, Digue L, Mercier C, et al: Recurrences following primary
osteosarcoma in adolescents and adults previously treated with
chemotherapy. Eur J Cancer 39:2050-2057, 2003

34. Kempf-Bielack B, Bielack SS, Jurgens H, et al: Osteosarcoma relapse
after combined modality therapy: an analysis of unselected patients in
the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol
23:559-568, 2005

35. Bielack SS, Kempf-Bielack B, Branscheid D, et al: Second and
subsequent recurrences of osteosarcoma: presentation, treatment, and
outcomes of 249 consecutive cooperative osteosarcoma study group
patients. J Clin Oncol 27:557-565, 2009

36. Palmerini E, Torricelli E, Cascinu S, et al: Is there a role for
chemotherapy after local relapse in high-grade osteosarcoma? Pediatr
Blood Cancer 66:e27792, 2019

37. Bacci G, Briccoli A, Longhi A, et al: Treatment and outcome of
recurrent osteosarcoma: experience at Rizzoli in 235 patients initially
treated with neoadjuvant chemotherapy. Acta Oncol 44:748-755, 2005

38. Briccoli A, Rocca M, Salone M, et al: Resection of recurrent
pulmonary metastases in patients with osteosarcoma. Cancer
104:1721-1725, 2005

39. Matsubara EM, T.; Koga, T.; Shibata, H.; Ikeda, K.; Shiraishi, K. \&
Suzuki, M.: Metastasectomy of pulmonary metastases from osteosarcoma:
Prognostic factors and indication for repeat metastasectomy. Journal of
Respiratory Medicine, 2015

40. Treasure T, Fiorentino F, Scarci M, et al: Pulmonary metastasectomy
for sarcoma: a systematic review of reported outcomes in the context of
Thames Cancer Registry data. BMJ Open 2, 2012

41. Treasure T, Milosevic M, Fiorentino F, et al: Pulmonary
metastasectomy: what is the practice and where is the evidence for
effectiveness? Thorax 69:946-949, 2014

42. Ferrari S, Briccoli A, Mercuri M, et al: Postrelapse survival in
osteosarcoma of the extremities: prognostic factors for long-term
survival. J Clin Oncol 21:710-715, 2003

43. Palmerini E, Setola E, Grignani G, et al: High Dose Ifosfamide in
Relapsed and Unresectable High-Grade Osteosarcoma Patients: A
Retrospective Series. Cells 9, 2020

44. Casali PG, Bielack S, Abecassis N, et al: Bone sarcomas:
ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis,
treatment and follow-up. Ann Oncol 29:iv79-iv95, 2018

45. Burgert EO, Jr., Nesbit ME, Garnsey LA, et al: Multimodal therapy
for the management of nonpelvic, localized Ewing's sarcoma of bone:
intergroup study IESS-II. J Clin Oncol 8:1514-1524, 1990

46. Nesbit ME, Jr., Gehan EA, Burgert EO, Jr., et al: Multimodal therapy
for the management of primary, nonmetastatic Ewing's sarcoma of bone: a
long-term follow-up of the First Intergroup study. J Clin Oncol
8:1664-1674, 1990

47. Miser JS, Kinsella TJ, Triche TJ, et al: Ifosfamide with mesna
uroprotection and etoposide: an effective regimen in the treatment of
recurrent sarcomas and other tumors of children and young adults. J Clin
Oncol 5:1191-1198, 1987

48. Grier HE, Krailo MD, Tarbell NJ, et al: Addition of ifosfamide and
etoposide to standard chemotherapy for Ewing's sarcoma and primitive
neuroectodermal tumor of bone. N Engl J Med 348:694-701, 2003

49. Paulussen M, Craft AW, Lewis I, et al: Results of the EICESS-92
Study: two randomized trials of Ewing's sarcoma
treatment--cyclophosphamide compared with ifosfamide in standard-risk
patients and assessment of benefit of etoposide added to standard
treatment in high-risk patients. J Clin Oncol 26:4385-4393, 2008

50. Le Deley MC, Paulussen M, Lewis I, et al: Cyclophosphamide compared
with ifosfamide in consolidation treatment of standard-risk Ewing
sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial.
J Clin Oncol 32:2440-2448, 2014

51. Womer RB, Daller RT, Fenton JG, et al: Granulocyte colony
stimulating factor permits dose intensification by interval compression
in the treatment of Ewing's sarcomas and soft tissue sarcomas in
children. Eur J Cancer 36:87-94, 2000

52. Womer RB, West DC, Krailo MD, et al: Randomized controlled trial of
interval-compressed chemotherapy for the treatment of localized Ewing
sarcoma: a report from the Children's Oncology Group. J Clin Oncol
30:4148-4154, 2012

53. Anderton J, Moroz V, Marec-Berard P, et al: International randomised
controlled trial for the treatment of newly diagnosed EWING sarcoma
family of tumours - EURO EWING 2012 Protocol. Trials 21:96, 2020

54. Brennan BK, L.; Marec-Berard, P.; Martin-Broto, J.M.; Gelderblom,
H.; Gasper, N.; Strauss, S.J.; Urgelles, A.S; Anderton, J.; Laurence,
V.; et al. : Comparison of two chemotherapy regimens in Ewing sarcoma
(ES): Overall and subgroup results of the Euro Ewing 2012 randmoized
trial (EE2012). . J. Clin. Oncol. 38:11500-11500, 2020

55. Schwartz CL, Wexler LH, Krailo MD, et al: Intensified Chemotherapy
With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic
Osteosarcoma: A Report From the Children's Oncology Group. Pediatr Blood
Cancer 63:54-61, 2016

56. Mascarenhas L, Felgenhauer JL, Bond MC, et al: Pilot Study of Adding
Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed
Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A
Report From the Children's Oncology Group. Pediatr Blood Cancer
63:493-498, 2016

57. Meyers PA, SR.; Slotkin, EK.; Dela Cruz, F. \& Wexier, LH.: The
addition of cycles of irinotecan/ temozolomide (i/T) to cycles of
vincristine, doxorubicin, cyclophosphamide (VDC) and cycles of
ifosfamide, etoposide (IE) for the treatment of Ewing sarcoma (ES).
Presented at the 2018 American Society of Clinical Oncology, May 20,
2018, 2018

58. Barker LM, Pendergrass TW, Sanders JE, et al: Survival after
recurrence of Ewing's sarcoma family of tumors. J Clin Oncol
23:4354-4362, 2005

59. Cotterill SJ, Ahrens S, Paulussen M, et al: Prognostic factors in
Ewing's tumor of bone: analysis of 975 patients from the European
Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol
18:3108-3114, 2000

60. Stahl M, Ranft A, Paulussen M, et al: Risk of recurrence and
survival after relapse in patients with Ewing sarcoma. Pediatr Blood
Cancer 57:549-553, 2011

61. McCabe MK, L.; Khan, M.; Fenwick, N.; Dirksen, U.; Gaspar, N.;
Kanerva, J.; Kuehne, T.; Longhi, A.; Luksch, R.; Mata, C.; Phillips, M.;
Safwat, A.; Strauss, S.; Sundby Hall, K.; Valverde Morales, CM.;
Westwood, AJ.; Winstanley, M.; Whelan, J. \& Wheatley, K.: Results of
the second interim assessment of rEECur, an international randomized
controlled trial of chemotherapy for the treatment of recurrent and
primary refractory Ewing sarcoma (RR-ES). Journal of Clinical Oncology
38:11502-11502, 2020

62. McCabe MM, V.; Khan, M.; Dirksen, U.; Evans, A.; Fenwick, N.;
Gaspar, N.; Kanerva, J.; Kuhne, T.; Longhi, A.; Luksch, R.; Mata, C.;
Phillips, M.; Sundby Hall, K.; Valverde Morales, CM.; Westwood, AJ.;
Winstanley, M.; Whelan, J. \& Wheatley, K.: Results of the first interim
assessment of rEECur, an international randomized controlled trial of
chemotherapy for the treatment of recurrent and primary refractory Ewing
sarcoma. American Society of Clinical Oncology 37:11007- 11007, 2019

63. Ahmed SK, Randall RL, DuBois SG, et al: Identification of Patients
With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report
From the Children's Oncology Group. Int J Radiat Oncol Biol Phys
99:1286-1294, 2017

64. Andreou D, Ranft A, Gosheger G, et al: Which Factors Are Associated
with Local Control and Survival of Patients with Localized Pelvic
Ewing's Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99
Trial. Clin Orthop Relat Res 478:290-302, 2020

65. Schuck A, Ahrens S, Paulussen M, et al: Local therapy in localized
Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86,
and EICESS 92 trials. Int J Radiat Oncol Biol Phys 55:168-177, 2003

66. Foulon S, Brennan B, Gaspar N, et al: Can postoperative radiotherapy
be omitted in localised standard-risk Ewing sarcoma? An observational
study of the Euro-E.W.I.N.G group. Eur J Cancer 61:128-136, 2016

67. Casey DL, Meyers PA, Alektiar KM, et al: Ewing sarcoma in adults
treated with modern radiotherapy techniques. Radiother Oncol
113:248-253, 2014

68. Gerrand C, Athanasou N, Brennan B, et al: UK guidelines for the
management of bone sarcomas. Clin Sarcoma Res 6:7, 2016

69. Balamuth NJ, Womer RB: Ewing's sarcoma. Lancet Oncol 11:184-192,
2010

70. Bernstein M, Kovar H, Paulussen M, et al: Ewing's sarcoma family of
tumors: current management. Oncologist 11:503-519, 2006

71. DuBois SG, Krailo MD, Gebhardt MC, et al: Comparative evaluation of
local control strategies in localized Ewing sarcoma of bone: a report
from the Children's Oncology Group. Cancer 121:467-475, 2015

72. Indelicato DJ, Keole SR, Shahlaee AH, et al: Definitive radiotherapy
for ewing tumors of extremities and pelvis: long-term disease control,
limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys
72:871-877, 2008

73. Donaldson SS: Ewing sarcoma: radiation dose and target volume.
Pediatr Blood Cancer 42:471-476, 2004

74. Ronchi L, Buwenge M, Cortesi A, et al: Whole Lung Irradiation in
Patients with Osteosarcoma and Ewing Sarcoma. Anticancer Res
38:4977-4985, 2018

75. Meyers PA, Schwartz CL, Krailo MD, et al: Osteosarcoma: the addition
of muramyl tripeptide to chemotherapy improves overall survival--a
report from the Children's Oncology Group. J Clin Oncol 26:633-638, 2008

76. Meyers PA, Schwartz CL, Krailo M, et al: Osteosarcoma: a randomized,
prospective trial of the addition of ifosfamide and/or muramyl
tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin
Oncol 23:2004-2011, 2005

77. Meyers PA: Muramyl tripeptide (mifamurtide) for the treatment of
osteosarcoma. Expert Rev Anticancer Ther 9:1035-1049, 2009

78. DeLaney TF, Park L, Goldberg SI, et al: Radiotherapy for local
control of osteosarcoma. Int J Radiat Oncol Biol Phys 61:492-498, 2005

79. Stacchiotti S, Sommer J, Chordoma Global Consensus G: Building a
global consensus approach to chordoma: a position paper from the medical
and patient community. Lancet Oncol 16:e71-83, 2015

80. Riedel RF, Larrier N, Dodd L, et al: The clinical management of
chondrosarcoma. Curr Treat Options Oncol 10:94-106, 2009

81. Ciernik IF, Niemierko A, Harmon DC, et al: Proton-based radiotherapy
for unresectable or incompletely resected osteosarcoma. Cancer
117:4522-4530, 2011

82. Oertel S, Blattmann C, Rieken S, et al: Radiotherapy in the
treatment of primary osteosarcoma--a single center experience. Tumori
96:582-588, 2010

83. DeLaney TF, Liebsch NJ, Pedlow FX, et al: Phase II study of
high-dose photon/proton radiotherapy in the management of spine
sarcomas. Int J Radiat Oncol Biol Phys 74:732-739, 2009

84. Ghosh KM, Lee LH, Beckingsale TB, et al: Indeterminate nodules in
osteosarcoma: what's the follow-up? Br J Cancer 118:634-638, 2018

85. Saifuddin A, Baig MS, Dalal P, et al: The diagnosis of pulmonary
metastases on chest computed tomography in primary bone sarcoma and
musculoskeletal soft tissue sarcoma. Br J Radiol:20210088, 2021

86. Cipriano C, Brockman L, Romancik J, et al: The Clinical Significance
of Initial Pulmonary Micronodules in Young Sarcoma Patients. J Pediatr
Hematol Oncol 37:548-553, 2015

87. Davison R, Hamati F, Kent P: What Effect Do Pulmonary Micronodules
Detected at Presentation in Patients with Osteosarcoma Have on 5-Year
Overall Survival? J Clin Med 10, 2021

88. Aryal A, Kumar VS, Shamim SA, et al: What Is the Comparative Ability
of 18F-FDG PET/CT, 99mTc-MDP Skeletal Scintigraphy, and Whole-body MRI
as a Staging Investigation to Detect Skeletal Metastases in Patients
with Osteosarcoma and Ewing Sarcoma? Clin Orthop Relat Res, 2021

89. Liu F, Zhang Q, Zhou D, et al: Effectiveness of (18)F-FDG PET/CT in
the diagnosis and staging of osteosarcoma: a meta-analysis of 26
studies. BMC Cancer 19:323, 2019

90. Palmerini E, Colangeli M, Nanni C, et al: The role of FDG PET/CT in
patients treated with neoadjuvant chemotherapy for localized bone
sarcomas. Eur J Nucl Med Mol Imaging 44:215-223, 2017

91. Rothermundt C, Seddon BM, Dileo P, et al: Follow-up practices for
high-grade extremity Osteosarcoma. BMC Cancer 16:301, 2016

92. Paioli A, Rocca M, Cevolani L, et al: Osteosarcoma follow-up: chest
X-ray or computed tomography? Clin Sarcoma Res 7:3, 2017

93. Puri A, Gulia A, Hawaldar R, et al: Does intensity of surveillance
affect survival after surgery for sarcomas? Results of a randomized
noninferiority trial. Clin Orthop Relat Res 472:1568-1575, 2014

94. Puri A, Ranganathan P, Gulia A, et al: Does a less intensive
surveillance protocol affect the survival of patients after treatment of
a sarcoma of the limb? updated results of the randomized TOSS study.
Bone Joint J 100-B:262-268, 2018

95. Campbell KM, Shulman DS, Grier HE, et al: Role of bone marrow biopsy
for staging new patients with Ewing sarcoma: A systematic review.
Pediatr Blood Cancer 68:e28807, 2021

96. Newman EN, Jones RL, Hawkins DS: An evaluation of
{[}F-18{]}-fluorodeoxy-D-glucose positron emission tomography, bone
scan, and bone marrow aspiration/biopsy as staging investigations in
Ewing sarcoma. Pediatr Blood Cancer 60:1113-1117, 2013

97. Cesari M, Righi A, Colangeli M, et al: Bone marrow biopsy in the
initial staging of Ewing sarcoma: Experience from a single institution.
Pediatr Blood Cancer 66:e27653, 2019

98. Inagaki C, Shimoi T, Sumiyoshi Okuma H, et al: Bone marrow
examination in patients with Ewing sarcoma/peripheral primitive
neuroectodermal tumor without metastasis based on
(18)F-fluorodeoxyglucose positron emission tomography/computed
tomography. Med Oncol 36:58, 2019

99. Kasalak O, Glaudemans A, Overbosch J, et al: Can FDG-PET/CT replace
blind bone marrow biopsy of the posterior iliac crest in Ewing sarcoma?
Skeletal Radiol 47:363-367, 2018

100. Kalus S, Saifuddin A: Whole-body MRI vs bone scintigraphy in the
staging of Ewing sarcoma of bone: a 12-year single-institution review.
Eur Radiol 29:5700-5708, 2019

101. Oberlin O, Rey A, Desfachelles AS, et al: Impact of high-dose
busulfan plus melphalan as consolidation in metastatic Ewing tumors: a
study by the Societe Francaise des Cancers de l'Enfant. J Clin Oncol
24:3997-4002, 2006

102. McTiernan A, Driver D, Michelagnoli MP, et al: High dose
chemotherapy with bone marrow or peripheral stem cell rescue is an
effective treatment option for patients with relapsed or progressive
Ewing's sarcoma family of tumours. Ann Oncol 17:1301-1305, 2006

103. Luksch R, Tienghi A, Hall KS, et al: Primary metastatic Ewing's
family tumors: results of the Italian Sarcoma Group and Scandinavian
Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and
total-lung irradiation. Ann Oncol 23:2970-2976, 2012

104. Ladenstein R, Potschger U, Le Deley MC, et al: Primary disseminated
multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin
Oncol 28:3284-3291, 2010

105. Whelan J, Le Deley MC, Dirksen U, et al: High-Dose Chemotherapy and
Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in
Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and
Ewing-2008. J Clin Oncol:JCO2018782516, 2018

106. Dirksen U, Brennan B, Le Deley MC, et al: High-Dose Chemotherapy
Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma
With Pulmonary Metastases: Results of the European Ewing Tumour Working
Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol
37:3192-3202, 2019

107. Dirksen UB, V.; Brichard, B.; Butterfass-Bahloul, T.; Cyprova, S.;
Faldum, A.; Gelderblom, H.; Hardes, J.; Hauser, P.; Havemann, L.;
Hjorth, L.; Juergens, H.; Kanerva, J.; Kuehne, T.; Ladenstein, RL.;
Raciborska, A.; Rascon, J.; Timmermann, B.; Ranft, A. \& Koch, R, on
behlaf of the Cooperative Ewing Sarcoma Study Group Ewing 2008.:
Efficacy of add-on treosulfan and melphalan high-dose therapy in
patients with high-risk metastatic Ewing sarcoma: Report from the
International Ewing 2008R3 trial. Journal of Clinical Oncology
38:11501-11501, 2020

108. Meyers PA, Krailo MD, Ladanyi M, et al: High-dose melphalan,
etoposide, total-body irradiation, and autologous stem-cell
reconstitution as consolidation therapy for high-risk Ewing's sarcoma
does not improve prognosis. J Clin Oncol 19:2812-2820, 2001

109. Yang X, Zhang L, Yang X, et al: Oncologic outcomes of pre- versus
post-operative radiation in Resectable soft tissue sarcoma: a systematic
review and meta-analysis. Radiat Oncol 15:158, 2020

110. Bedetti B, Wiebe K, Ranft A, et al: Local control in Ewing sarcoma
of the chest wall: results of the EURO-EWING 99 trial. Ann Surg Oncol
22:2853-2859, 2015

111. Vogin G, Helfre S, Glorion C, et al: Local control and sequelae in
localised Ewing tumours of the spine: a French retrospective study. Eur
J Cancer 49:1314-1323, 2013

112. Bekelman JE, Schultheiss T, Berrington De Gonzalez A: Subsequent
malignancies after photon versus proton radiation therapy. Int J Radiat
Oncol Biol Phys 87:10-12, 2013

113. Merchant TE: Clinical controversies: proton therapy for pediatric
tumors. Semin Radiat Oncol 23:97-108, 2013

114. Chung CS, Yock TI, Nelson K, et al: Incidence of second
malignancies among patients treated with proton versus photon radiation.
Int J Radiat Oncol Biol Phys 87:46-52, 2013

115. Leroy R, Benahmed N, Hulstaert F, et al: Proton Therapy in
Children: A Systematic Review of Clinical Effectiveness in 15 Pediatric
Cancers. Int J Radiat Oncol Biol Phys 95:267-278, 2016

116. Rombi B, DeLaney TF, MacDonald SM, et al: Proton radiotherapy for
pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol
Biol Phys 82:1142-1148, 2012

117. Sklar C: Maintenance of ovarian function and risk of premature
menopause related to cancer treatment. J Natl Cancer Inst Monogr:25-27,
2005

118. Critchley HO, Wallace WH: Impact of cancer treatment on uterine
function. J Natl Cancer Inst Monogr:64-68, 2005

119. Gross E, Champetier C, Pointreau Y, et al: {[}Normal tissue
tolerance to external beam radiation therapy: ovaries{]}. Cancer
Radiother 14:373-375, 2010

120. Haie-Meder C, Mlika-Cabanne N, Michel G, et al: Radiotherapy after
ovarian transposition: ovarian function and fertility preservation. Int
J Radiat Oncol Biol Phys 25:419-424, 1993

121. Yamada Y, Lovelock DM, Yenice KM, et al: Multifractionated
image-guided and stereotactic intensity-modulated radiotherapy of
paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys
62:53-61, 2005

122. Nevelsky A, Borzov E, Daniel S, et al: Perturbation effects of the
carbon fiber-PEEK screws on radiotherapy dose distribution. J Appl Clin
Med Phys 18:62-68, 2017

123. Barnett JR, Gikas P, Gerrand C, et al: The sensitivity,
specificity, and diagnostic accuracy of whole-bone MRI for identifying
skip metastases in appendicular osteosarcoma and Ewing sarcoma. Skeletal
Radiol 49:913-919, 2020

124. Theruvath AJ, Siedek F, Muehe AM, et al: Therapy Response
Assessment of Pediatric Tumors with Whole-Body Diffusion-weighted MRI
and FDG PET/MRI. Radiology 296:143-151, 2020

125. Nicoli F, Saleh DB, Ragbir M, et al: Response to: Comment on
''Intraoperative Near-infrared Fluorescence (NIR) Imaging with
Indocyanine Green (ICG) Can Identify Bone and Soft Tissue Sarcomas which
May Provide Guidance for Oncological Resection''. Ann Surg, 2020

126. Laitinen MK, Parry MC, Albergo JI, et al: Is computer navigation
when used in the surgery of iliosacral pelvic bone tumours safer for the
patient? Bone Joint J 99-B:261-266, 2017

127. Tate R, Gerrand C, Hale J: Tibial turn-up procedure as an
alternative to rotationplasty in a 4-year-old with osteosarcoma of the
distal femur. J Pediatr Orthop B 24:50-55, 2015

128. Hebert JS, Rehani M, Stiegelmar R: Osseointegration for Lower-Limb
Amputation: A Systematic Review of Clinical Outcomes. JBJS Rev 5:e10,
2017

129. Jeys LM, Thorne CJ, Parry M, et al: A Novel System for the Surgical
Staging of Primary High-grade Osteosarcoma: The Birmingham
Classification. Clin Orthop Relat Res 475:842-850, 2017

130. Fujiwara T, Medellin MR, Sambri A, et al: Preoperative surgical
risk stratification in osteosarcoma based on the proximity to the major
vessels. Bone Joint J 101-B:1024-1031, 2019

131. Mumith A, Coathup M, Chimutengwende-Gordon M, et al: Augmenting the
osseointegration of endoprostheses using laser-sintered porous collars:
an in vivo study. Bone Joint J 99-B:276-282, 2017

132. Parry MC, Laitinen MK, Albergo JI, et al: Silver-coated (Agluna(R))
tumour prostheses can be a protective factor against infection in high
risk failure patients. Eur J Surg Oncol 45:704-710, 2019

133. Bleyer A, Tai E, Siegel S: Role of clinical trials in survival
progress of American adolescents and young adults with cancer-and lack
thereof. Pediatr Blood Cancer 65:e27074, 2018

134. Ferrari A, Stark D, Peccatori FA, et al: Adolescents and young
adults (AYA) with cancer: a position paper from the AYA Working Group of
the European Society for Medical Oncology (ESMO) and the European
Society for Paediatric Oncology (SIOPE). ESMO Open 6:100096, 2021

135. Gaspar N, Marshall LV, Binner D, et al: Joint adolescent-adult
early phase clinical trials to improve access to new drugs for
adolescents with cancer: proposals from the multi-stakeholder
platform-ACCELERATE. Ann Oncol 29:766-771, 2018

136. Davis LE, Bolejack V, Ryan CW, et al: Randomized Double-Blind Phase
II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin
Oncol 37:1424-1431, 2019

137. Duffaud F, Mir O, Boudou-Rouquette P, et al: Efficacy and safety of
regorafenib in adult patients with metastatic osteosarcoma: a
non-comparative, randomised, double-blind, placebo-controlled, phase 2
study. Lancet Oncol 20:120-133, 2019

138. Attia SB, V.; Ganjoo, KN.; George, S.; Agulnik, M.; Rushing, DA.;
Loggers, ET.; Livingston, MB.; Wright, JA.; Chawla, SP.; Okuno, SH.;
Reinke, DK.; Riedel, RF.; Davis, LE.; Ryan, CW. \& Maki, RG.: A phase II
trial of regorafenib (REGO) in patients (pts) with advanced Ewing
sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial
results. Presented at the ASCO, May 20, 2017

139. Duffaud FB, J.; Mir, O.; Chevreau, CM.; Boudou Rouquette, P.;
Kalbacher, E.; Penel, N.; Perrin, C.; Laurence, V.; Bompas, E.;
Saada-Bouzid, E.; Delcambre, C.; Bertucci, F.; Cancel, M.; Schiffler,
C.; Monard, L.; Bouvier, C.; Vidal, C.; Gasper, N. \& Chabaud, S.: LBA68
- Results of the randomized, placebo (PL)-controlled phase II study
evaluating the efficacy and safety of regorafenib (REG) in patients
(pts) with metastatic relapsed Ewing sarcoma (ES), on behalf of the
French Sarcoma Group (FSG) and UNICANCER. Presented at the ESMO virtual
conference 2020., 20 Sept 2020, 2020

140. Italiano A, Mir O, Mathoulin-Pelissier S, et al: Cabozantinib in
patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a
multicentre, single-arm, phase 2 trial. Lancet Oncol 21:446-455, 2020

141. Xie L, Xu J, Sun X, et al: Apatinib for Advanced Osteosarcoma after
Failure of Standard Multimodal Therapy: An Open Label Phase II Clinical
Trial. Oncologist 24:e542-e550, 2019

142. Gaspar NBS, FJ.; Venkatramani, R.; Longhi, A.; Lervat, C.;
Casanova, M.; Aerts, I.; Bielack, SS.; Entz-Werle, N.; Strauss, S.; He,
C.; Thebaud, E.; Locatelli, F.; Morland, B.; Gallego Melcon, S.; Canete
Nieto, A.; Marec-Berard, P.; Gambart, M.; Rossig, C. \& Campbell-
Hewson, Q.: Phase I combination dose-finding/phase II expansion cohorts
of lenvatinib + etoposide + ifosfamide in patients (pts) aged 2 to[?]25
years with relapsed/refractory (r/r) osteosarcoma. Presented at the
European Society for Medical Oncology (ESMO), 2019

143. Brenner JC, Feng FY, Han S, et al: PARP-1 inhibition as a targeted
strategy to treat Ewing's sarcoma. Cancer Res 72:1608-1613, 2012

144. Choy E, Butrynski JE, Harmon DC, et al: Phase II study of olaparib
in patients with refractory Ewing sarcoma following failure of standard
chemotherapy. BMC Cancer 14:813, 2014

145. Schafer ES, Rau RE, Berg SL, et al: Phase 1/2 trial of talazoparib
in combination with temozolomide in children and adolescents with
refractory/recurrent solid tumors including Ewing sarcoma: A Children's
Oncology Group Phase 1 Consortium study (ADVL1411). Pediatr Blood Cancer
67:e28073, 2020

146. Chugh R, Ballman KV, Helman LJ, et al: SARC025 arms 1 and 2: A
phase 1 study of the poly(ADP-ribose) polymerase inhibitor niraparib
with temozolomide or irinotecan in patients with advanced Ewing sarcoma.
Cancer 127:1301-1310, 2021

147. Smith MA, Reynolds CP, Kang MH, et al: Synergistic activity of PARP
inhibition by talazoparib (BMN 673) with temozolomide in pediatric
cancer models in the pediatric preclinical testing program. Clin Cancer
Res 21:819-832, 2015

148. Engert F, Kovac M, Baumhoer D, et al: Osteosarcoma cells with
genetic signatures of BRCAness are susceptible to the PARP inhibitor
talazoparib alone or in combination with chemotherapeutics. Oncotarget
8:48794-48806, 2017

149. Holme H, Gulati A, Brough R, et al: Chemosensitivity profiling of
osteosarcoma tumour cell lines identifies a model of BRCAness. Sci Rep
8:10614, 2018

150. Jones DTW, Banito A, Grunewald TGP, et al: Molecular
characteristics and therapeutic vulnerabilities across paediatric solid
tumours. Nat Rev Cancer 19:420-438, 2019

151. Tawbi HA, Burgess M, Bolejack V, et al: Pembrolizumab in advanced
soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre,
two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol
18:1493-1501, 2017

152. D'Angelo SP, Mahoney MR, Van Tine BA, et al: Nivolumab with or
without ipilimumab treatment for metastatic sarcoma (Alliance A091401):
two open-label, non-comparative, randomised, phase 2 trials. Lancet
Oncol 19:416-426, 2018

153. Paoluzzi L, Cacavio A, Ghesani M, et al: Response to anti-PD1
therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res 6:24,
2016

154. Sundara YT, Kostine M, Cleven AH, et al: Increased PD-L1 and T-cell
infiltration in the presence of HLA class I expression in metastatic
high-grade osteosarcoma: a rationale for T-cell-based immunotherapy.
Cancer Immunol Immunother 66:119-128, 2017

155. Dobrenkov K, Ostrovnaya I, Gu J, et al: Oncotargets GD2 and GD3 are
highly expressed in sarcomas of children, adolescents, and young adults.
Pediatr Blood Cancer 63:1780-1785, 2016

156. Wingerter A, El Malki K, Sandhoff R, et al: Exploiting Gangliosides
for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline
Glioma. Cancers (Basel) 13, 2021

157. Mody R, Yu AL, Naranjo A, et al: Irinotecan, Temozolomide, and
Dinutuximab With GM-CSF in Children With Refractory or Relapsed
Neuroblastoma: A Report From the Children's Oncology Group. J Clin Oncol
38:2160-2169, 2020

158. Erkizan HV, Kong Y, Merchant M, et al: A small molecule blocking
oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits
growth of Ewing's sarcoma. Nat Med 15:750-756, 2009

159. Zollner SK, Selvanathan SP, Graham GT, et al: Inhibition of the
oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and
enhanced vincristine sensitivity in Ewing's sarcoma. Sci Signal 10, 2017

160. Ludwig JF, NC.; Anderson, PM.; Macy, ME.; Riedel, RF.; Davis, LE.;
Daw, NC.; Wulff, J.; Kim, A.; Ratan, R.; Baskin-Bey, ES.; Toretsky, JA.;
Breitmeyer, JB. \& Meyers, PA.: TK216 for relapsed/ refractory Ewing
sarcoma: Interim phase 1/2 results. Journal of Clinical Oncology
39:11500-11500, 2021

161. Surveillance, Epidemiology, and End Results (SEER) Program
(www.seer.cancer.gov) SEER*Stat Database: Incidence- SEER Research Data,
9 Registries, Nov 2019 Sub (1975-2017)- Linked to County Attributes-
Time Dependent (1990- 2017) Income/ Rurality, 1969- 2018 Counties,
National Cancer Institute, DCCPS, Surveillance Research Program,
released April 2020, based on the November 2019 submission.

162. Joinpoint Regression Program, Version 4.6.0.0. April, 2018;
Statistical Research and Applications Branch, National Cancer Institute.
Statistical Research and Applications Branch, National Cancer Institute.
Kim HJ, Fay MP, Feuer, EJ, Midthune DN. Permutation tests for joinpoint
regression with applications to cancer rates. Stat Med 2000; 19:335-351
(correction: 2001;20:655).

163. Granowetter L, Womer R, Devidas M, et al: Dose-intensified compared
with standard chemotherapy for nonmetastatic Ewing sarcoma family of
tumors: a Children's Oncology Group Study. J Clin Oncol 27:2536-2541,
2009

164. Le Grange F: Advanced radiotherapy techniques: Improving outcomes
in sarcoma., UCL (University College London), UCL Discovery., 2021

165. Gaspar NC, M.; Bautista Sirvent, FJ.; Venkatramani, R.; Morland,
B.; Gambart, M.; Thebaud, E.; Strauss, S.; Locatelli, F.; Melcon, SG.;
Canete, A.; Bielack, SS.; Rossig, C.; Aerts, I.; Marec-Berard, P.;
Kraljevic, S.; Hayato, S.; He, C.; Dutcus, CE. \& Campbell-Hewson, Q.:
Single-agent expansion cohort of lenvatinib (LEN) and combination
dose-finding cohort of LEN + etoposide (ETP) + ifosfamide (IFM) in
patients (pts) aged 2 to [?]25 years with relapsed/refractory osteosarcoma
(OS). Journal of Clinical Oncology 36:11527-11527, 2018

166. Federico SM, Pappo AS, Sahr N, et al: A phase I trial of
talazoparib and irinotecan with and without temozolomide in children and
young adults with recurrent or refractory solid malignancies. Eur J
Cancer 137:204-213, 2020

\textbf{Figure legends}

\textbf{Figure 1. The incidence and outcomes of primary bone sarcoma
using Surveillance, Epidemiology, and End Results (SEER) data.}

\textbf{A-C.} The incidence trends of bone sarcoma, SEER 21, overall
from 2000 to 2017- histological type, gender and ethnicity by age of
diagnosis. Data from SEER.\textsuperscript{2} \textbf{D.} Five-year
relative survival rates for osteosarcoma and Ewing sarcoma, SEER9, from
patients diagnosed between 1975 to 2012 with at least 5-years follow-up
for survival analyses. Data from SEER.\textsuperscript{161,162}

\textbf{Figure 2. Example PBT plans for pelvic and sacral tumors in
AYAs.\textsuperscript{164}}

Axial and coronal images of two definitive PBT plans to treat locally
advanced pelvic ES. An iliac bone primary in a 16-year-old female
(\textbf{A-B} ) and sacral tumor in a 19-year-old female (\textbf{C-D}
). Red colour wash represents high dose, green moderate and blue the low
dose.

\textbf{Figure 3. Surgical techniques for primary bone sarcoma.}

\textbf{A} . Complex navigation plan showing proposed resection planes
for low grade osteosarcoma of the iliac wing. \textbf{B} .
Reconstruction of the hip after navigated extraarticular resection using
modular porous acetabular reconstruction system. \textbf{C} . 3D printed
custom jig for resection of femoral diaphyseal Ewing sarcoma before
insertion of custom implant.

\textbf{Hosted file}

\verb`Table I.docx`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Hosted file}

\verb`TABLE II.docx`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Hosted file}

\verb`Fig 1.pptx`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Hosted file}

\verb`PBT in AYA.pptx`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

\textbf{Hosted file}

\verb`10June_Surgical pics.pptx`  available at \url{https://authorea.com/users/420892/articles/527132-current-approaches-to-management-of-bone-sarcoma-in-adolescent-and-young-adult-aya-patients}

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

