ejc supplements 10, no.

1 (2012) 160166
Achievements of the EORTC Soft Tissue and Bone Sarcoma
Group
Peter Hohenberger
a,
*, Martine van Glabbeke
b
, Monia Ouali
b
, Ian Judson
c
a
Mannheim University Medical Center, Mannheim, Germany
b
EORTC Headquarters, Brussels, Belgium
c
Royal Marsden Hospital, London, United Kingdom
article info
Keywords:
Sarcoma
Soft tissue
Bone
Clinical research
Translational research
abstract
The EORTC Soft Tissue and Bone Sarcoma Group (STBSG) develops, stimulates, and
coordinates studies on all aspects of sarcomas, and over the years they have made
signicant achievements in the research and treatment of sarcomas. Through EORTC
trials 62001, 62005, 62024, and 62063, they established imatinib in the treatment
of gastrointestinal stromal tumors (GIST). Because the STBSG has conducted a
large number of clinical trials in advanced disease and collected and stored all
trial data in a consistent format, they were able to use these data in retrospective
studies and develop progression-free survival as the primary endpoint for phase II
studies in advanced soft-tissue sarcoma. This database also served as a basis for
research projects analyzing subgroups of tumors like malignant peripheral nerve
sheath tumors, and for exploring prognostic and predictive factors for rst-line
chemotherapy including ifosfamide, and proved to be of value when analyzing the
results of adjuvant chemotherapy in adolescents and young adults as compared to
the adult patient population. This article describes these achievements and looks
into the future strategy of the STBSG.
2012 European Organisation for Research and Treatment of Cancer. All rights reserved.
1. Introduction
The objectives of the EORTC Soft Tissue and Bone
Sarcoma Group (STBSG) are to develop, stimulate and
coordinate studies on all aspects of sarcomas within
the framework of the EORTC. This is done by organizing
clinical trials and regular investigator meetings as well
as conferences and symposia to promote such studies.
At present, STBSG has 54 member institutions from
14 countries. It is an interdisciplinary group with medical
oncologists, radiation oncologists, surgical oncologists,
* Corresponding author. Prof. Peter Hohenberger, MD, Divi-
sion of Surgical Oncology & Thoracic Surgery, Mannheim
University Medical Center, University of Heidelberg, Theodor
Kutzer Ufer 13, D-68167 Mannheim, Germany
pathologists, radiologists, geneticists and biologists as
well as statisticians contributing to trial-oriented and
translational research. The group was founded in
September 1976 and the rst patient was recruited into
EORTC trial 62761 four weeks later. In September 1978,
the group fused with the International Osteosarcoma
Group and received its present name. Initial founders
included Gianni Bonadonna, Daniel Crowther, Allan van
Oosterom, Bob Pinedo, Siegfried Seber, Hans-J org Senn,
Richard Silvester, and J.A.M. van Unnik.
Some unique trials in the eld of sarcoma were
performed within STBSG. The largest adjuvant study in
sarcoma ever performed recruited 351 patients (EORTC
trial 62931). The role of deep-wave hyperthermia added
to a systemic chemotherapy in the neoadjuvant setting
of locally advanced sarcomas was studied in a phase III
1359-6349/$ see front matter 2012 European Organisation for Research and Treatment of Cancer. All rights reserved.
ejc supplements 10, no. 1 (2012) 160166 161
trial.
1
The group conducted the largest study to com-
pare single-agent doxorubicin versus doxorubicin plus
ifosfamide as rst-line therapy for metastatic soft-tissue
sarcoma (EORTC trial 62012). The role of limited dose of
radiation therapy in aggressive bromatosis/desmoids, a
very rare subset of sarcoma patients, was studied and
will report soon after long-term follow up (EORTC trial
62991). The group also conducted the largest transla-
tional research project worldwide in radiation-induced
sarcomas (TR01/01). As a more classical approach, the
group conducted over 20 phase I and phase II trials to
evaluate many individual drugs and drug combinations
to analyze response and survival in advanced sarcoma.
There are three major aspects of these trials that
deserve closer attention.
2. Imatinib in gastro-intestinal stromal tumors
(GIST)
Everybody is aware of the dramatic improvement in
overall survival (OS) in patients with metastatic GIST
since imatinib became available, and the STBSG was
involved in the development of this drug from the very
beginning. A phase I study was conducted to identify
the dose-limiting effects in patients with advanced
soft-tissue sarcomas including GIST and showed that
a dose of 400 mg twice daily was well tolerated with
diminishing side-effects during continuous treatment.
CT scans revealed that major regression of the tumor was
induced and FDG-uptake was dramatically decreased.
More than three fourths of the patients were still on
treatment after more than 9 months which was a unique
result of a phase I study,
2
and a later update of the
study showed that more than 80% of the patients had
clinically important benet which changed the treatment
landscape dramatically (Fig. 1).
The phase II study (EORTC trial 62001) followed imme-
diately and showed that in a chemotherapy pretreated
group of patients suffering from advanced GIST and soft-
tissue sarcoma, the GIST patients benetted greatly with
73% of the patients being free from progression at one
year.
3
In contrast, there were no objective responses
in the other soft-tissue sarcoma group. The conclusion
still holds today that the dose of 800 mg imatinib is
highly active in patients with KIT-positive GIST, but
patients with other soft-tissue sarcomas unselected for
a molecular target are unlikely to benet.
Concurrent with 62001 a randomised phase II study in
the USA, B2222, treated GIST patients with either 400 mg
or 600 mg daily and similar activity was reported.
4
The
STBSG, joined by the Australasian Gastro-Intestinal Trials
Group (AGITG) and the Italian Sarcoma Group performed
a phase III study (EORTC trial 62005), comparing 400 mg
versus 800 mg of imatinib, and 946 patients from
13 countries were recruited in less than a year! The
STBSG selected to use progression-free survival (PFS) as
(Months)
0 6 12 18 24 30
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :
Treatment
273 946 850 786 638 393
79 86 57 31 19 14
Imatinib
Dox.based
%

o
f

p
a
t
i
e
n
t
s

a
l
i
v
e
Fig. 1 Overall survival of patients with gastro-intestinal
stromal tumors comparing imatinib versus doxorubicin
based chemotherapy used before 2001.
5
Reprinted from
The Lancet, Vol. 364, Verweij J, Casali PG, Zalcberg J,
et al. Progression-free survival in gastrointestinal stro-
mal tumours with high-dose imatinib: randomised trial,
pp. 112734, Copyright 2004, with permission from
Elsevier.
the primary endpoint of this study, whereas the North-
American trial looked at OS as the primary endpoint and
recruited 746 patients. In study 62005 there was no sig-
nicant difference in response to treatment according to
imatinib dose, however, the higher 800 mg dose achieved
signicantly longer PFS.
5
Our studies suggested that the
PFS benet was largely derived from patients with the
rare exon 9 mutation in KIT.
6
While this difference was
not apparent in the North-American study, which had
a much smaller number of exon 9 mutant patients,
a meta-analysis of both the EORTC 62005 and S0033
data sets conrmed the signicantly improved PFS seen
in the exon 9 patients using the 800 mg dose, while
no such effect was seen in the patients with exon 11
mutations. Consequently, the treatment starting dose
for imatinib is 400 mg in all patients except those with
tumors harboring exon 9 mutations, who require 800 mg
of imatinib for optimal benet.
7
The molecular data of the study using pretreatment
samples were analyzed for mutations of KIT and PDGFR-a
and the mutation types were correlated with the survival
data of the patients. It turned out that the exon 9
activating mutation of KIT was the strongest adverse
prognostic factor for response, including a relative risk
of progression of 171% when compared to exon 11
mutations.
6,8
Those patients proted from the high-dose
regimen with a signicantly improved PFS rate and a
reduction of the relative risk to a hazard ratio of 0.61.
This study for the rst time concluded that in a solid
tumor the genotype is of major prognostic signicance
for PFS and OS.
Molecular data as well as immunohistochemistry were
used to analyze the effect of the immuno-histochemical
phenotype of the tumor on PFS or OS, but did not
162 ejc supplements 10, no. 1 (2012) 160166
show any correlations.
9
However, the study material
contributed to the evaluation of a new marker (DOG1) in
GIST and proved that a combination of CD117 and DOG1-
immunostaining is sufcient to conrm the histological
diagnosis of a GIST and separate it from other spindle
cell malignancies.
10
A tissue microarray project on 353
samples from the phase III study was used to analyze the
expression pattern of cell cycle and apoptosis regulators.
Impaired p53, p16, BCL2, and CHK2 expression was
common in advanced GIST and cell cycle/apoptosis
maintenance is instrumental for optimal response to
imatinib.
11
Further studies focused on determinants of imatinib
efcacy. A thorough analysis of pharmacokinetics re-
vealed a trend towards increased imatinib clearance after
chronic exposure of more than 12 months.
12
There was
no effect of cigarette smoking on the pharmacokinetics
of imatinib, however, smokers with GIST showed a
shorter OS and time to progression.
13
Further studies
addressed a concern that imatinib might be cardiotoxic,
showing that only 0.2% of the patients after nearly
25,000 exposures had possible cardiac side-effects.
14
An analysis of the correlation between toxicities of
CTC grade II or more with imatinib dose, age, sex,
performance status, disease site, and size of lesions at
trial entry led to a multivariate risk calculator that can be
used in the clinics for individual patients and is available
at the EORTC website.
15
Also, different prognostic factors
for initial and late resistance to imatinib in advanced
GIST could be evaluated.
16
Very important was the report on the analysis whether
tumor response to imatinib contributes to a better
survival in comparison to patients achieving just
stable disease, as might be claimed with cytotoxic
chemotherapy. However, in the treatment of GIST
with imatinib, it did not matter whether patients
developed a CR, PR, or MR, or even no change; all
treatment responses resulted in similar PFS and OS. After
6 months of imatinib, responders by RECIST had the
same survival outcome as patients classied as stable
disease. Only patients experiencing progressive disease
had signicantly worse outcome.
17
These ndings are of
major importance in accepting PFS as a primary endpoint
in patients with soft-tissue sarcoma in the metastatic
setting when treated with tyrosine kinase inhibitors.
Following the development of the drug in metastatic
patients, STBSG also started the largest adjuvant study
in patients with intermediate and high-risk GIST (EORTC
trial 62024) comparing two years of treatment versus
observation. Unfortunately, the usual primary endpoint
for an adjuvant trial, OS, turned out to be problematic.
Treatment for metatastic GIST after relapse from prior
adjuvant therapy can successfully salvage the majority
of patients and it could take more than 10 years until
the primary endpoint is evaluable. After recruiting more
than 900 patients to this study, the primary endpoint
has been changed to time to imatinib failure in those
patients who received imatinib in the adjuvant setting
and subsequently again on progression, to provide an
earlier readout of treatment benet. The group was
deeply involved in the discussion on how to interpret the
data of the ACOSOG Z9001 adjuvant study showing that
one year of imatinib signicantly improved PFS but did
not translate into an improvement of OS, at least partly
because of unblinding and cross-over, and probably
represents under-treatment for patients with a high risk
of recurrence.
18
In a joint effort with the EU-funded network Conti-
canet, the reporting tools on the surgery for the primary
tumor were evaluated by thoroughly comparing the
source data of the original operative record and the
original pathology report with the data used for patient
study entry. STBSG has constructed a reporting tool to
enable adequate documentation of the initial ndings
and measures which is now available for other study
groups.
19
In continuing the evaluation of imatinib, STBSG in
collaboration with SWOG proved the efcacy of the
drug in an extremely rare sarcoma subtype, dermato-
brosarcoma protuberans, by pooling the data of two
separate phase II-studies. Again, the molecular target of
a translocation t[17;22] involving the PDGFR-b gene is the
decisive element for imatinib treatment success.
20
3. Developing PFS as a primary endpoint in trials
Only a few cytotoxic agents have demonstrated activity
against advanced soft-tissue sarcoma (e.g. doxorubicin,
ifosfamide, dacarbazine); in most cases, the treatment
is palliative, and only 8% of patients are still alive
5 years after start of rst-line chemotherapy. Most of the
conrmed and investigational anticancer agents studied
in the last 50 years have been explored in soft-tissue
sarcoma, but few have shown any substantial activity
in terms of objective responses.
21
However, a few drugs
(e.g. trabectedin) have induced some unexpected long
disease stabilizations. One of the explanations for those
disappointing (but not completely negative) results may
lie in the large heterogeneity of soft-tissue sarcoma, in
terms of histology (the current classication includes
more than 50 histological subtypes) and anatomic
presentation (virtually all sites of the human body).
Another explanation may be the traditional choice
of objective response to therapy (documentation of a
decrease in tumor load) as primary endpoint for drug
screening studies, which does not reect the mechanism
of action of cytostatic agents.
Endpoints based on disease stabilization rather than
objective responses are obviously more appropriate for
those agents, but cut-off values would be needed to
distinguish active from non-active drugs. Indeed, if the
ejc supplements 10, no. 1 (2012) 160166 163
(months) 0 3 6 9 12 15
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :
221 234 47 16 5 1
136 146 55 18 14 11
Inactive agents
Active agents
Fig. 2 Progression-free rate of chemotherapeutic agents in second-line treatment after doxorubicin rst-line therapy
separating active from inactive agents.
22
Reprinted from Eur J Cancer, Vol. 38, van Glabbeke M, Verweij J, Judson I, Nielsen OS.
Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas, pp. 5439, Copyright 2002, with
permission from Elsevier.
tumor size has not objectively increased after a pre-
dened time period, this can be due either to the
activity of the drug or simply to the slow growth of the
original tumor. Therefore, a small proportion of disease
stabilizations (according to standard criteria, like WHO
or RECIST) is to be expected, even with inactive agents or
combinations, while the expected proportion of objective
responses is close to zero.
The STBSG has conducted a large number of clinical
trials in advanced disease and collected and stored
all trial data in a consistent format. The histology of
most cases has been reviewed by an international panel
of experts. Consequently, the group has accumulated
a database of more than 3000 patients which can be
used for retrospective studies. We have proposed to use
the progression-free status at a xed time point (3 or
6 months after treatment start) as the primary endpoint
for phase II studies in advanced soft-tissue sarcoma
22
(Fig. 2). To use this criterion we need estimates in the
studied patient population of the proportion of patients
still expected to be progression-free after treatment with
an inactive agent and after treatment with an active
agent or regimen (reference values for the statistical
design). Those two proportions should be different
enough to limit the sample size of the trial (preferably
at least 15% apart). We have used the STBSG database to
estimate this proportion in various groups of patients.
For patients treated after failure of the rst-line
chemotherapy regimen, we used the data from 12
STBSG clinical trials, including 146 patients treated
with an active regimen (ifosfamide or dacarbazine), and
234 patients treated with an inactive regimen (nine
investigational drugs); 39% of the patients from the rst
group were progression free after 3 months, while this
gure was only 21% for patients of the second group.
We concluded that the difference was large enough to
use the 3-month progression-free rate as the primary
endpoint to screen new agents used as 2nd- or 3rd-line
therapy for advanced disease, and that the estimations
of the progression-free rate with active and with inactive
agents were precise enough (standard error <5%) to be
used as reference values in classical phase II designs.
For patients treated with a rst-line chemotherapy
regimen, we used a database of 1154 patients, all
treated with an active anthracycline-based regimen.
The size of the database was sufcient to provide
reference values for the principal histological subtypes;
leiomyosarcoma (n=531), MFH/NOS (n=217), synovial
sarcoma (n=115), neurogenic sarcoma (n=113), liposar-
coma (n=110), brosarcoma (n=68). Estimations of the
6-month progression-free rates varied between 30% and
56% in the different subgroups, and between 44% and
77% for the 3-month progression-free rate; the standard
error was 6% or less for all estimates.
Those reference values have become extremely useful
for new drug screening. The success of imatinib mesylate
in GIST has raised the hope that other targeted therapies
could show activity in other types of sarcoma. As those
drugs are essentially cytostatic, objective response to
therapy is not an appropriate screening endpoint, and
progression-free rate offers a valid alternative. This
endpoint has been used by the STBSG to demonstrate the
activity of pazopanib and of eribulin (EORTC trial 62052)
23
in phase II trials conducted in different histological
subtypes of soft-tissue sarcoma and has resulted in the
exclusion of certain sarcoma subtypes from subsequent
164 ejc supplements 10, no. 1 (2012) 160166
Fig. 3 Time to progression in patients with sarcoma subtypes used as strata in the phase II study 62043 evaluating
pazopanib as a second-line treatment in advanced soft-tissue sarcoma.
27
Reprinted from J Clin Oncol, Vol. 27, Sleijfer S, Ray-
Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced
soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue
and Bone Sarcoma Group (EORTC study 62043), pp. 312632, Copyright 2009, with permission from the American Society of
Clinical Oncology.
phase III studies. However, a denitive demonstration
of the therapeutic efcacy of new drugs still requires
appropriate testing in comparative randomized phase III
clinical trials, like the PALETTE trial (Phase III trial
of pazopanib vs placebo in patients who had failed
anthracycline-based therapy).
4. Exploiting the database of patients treated in
group studies
The database described above was not only used to
generate reference curves for PFS and OS in new
drugs. It also served as a basis for research projects
analyzing subgroups of tumors like malignant peripheral
nerve sheath tumors (MPNST) in which the role of
chemotherapy was unclear. 175 MPNST out of 2675
eligible STS patients were analyzed and it turned out that
outcome was similar for MPNST versus other sarcoma
subtypes. Performance status was an independent
prognostic factor for OS and the chemotherapy regimen
was an independent prognostic factor for response, with
doxorubicinifosfamide producing the best response.
24
The database was also used to explore prognostic and
predictive factors for rst-line chemotherapy including
ifosfamide. For this purpose, a retrospective, exploratory
analysis was performed on data from 1337 advanced STS
patients who received rst-line ifosfamide-containing
chemotherapy; 660 patients treated with doxorubicin
monotherapy served as comparators. The study provided
important information for the interpretation and design
of clinical trials for specic sarcoma subtype entities and
may contribute to further treatment individualisation of
advanced STS patients.
25,26
A very successful application
of these criteria and the discrimination of active
versus inactive drugs in second-line studies was used
when developing pazopanib, a multikinase angiogenesis
inhibitor. After the phase II study with the strata
of liposarcoma, synovial sarcoma, leiomyosarcoma and
other sarcoma subtypes had shown that for liposarcoma
patients the threshold of an active drug was not
met (Fig. 3), those patients were excluded from the
subsequent and very successful phase III study.
27
The database also proved to be of major value
when analyzing the results of adjuvant chemotherapy
in the adolescent and young adult (1529 years, AYA
population) versus the adult patient group (30 years).
We conducted a retrospective study, pooling data from
two randomized trials of adjuvant chemotherapy in STS
(EORTC trial 62771 and 62931). A total of 793 patients
were included with a median follow-up of 8.74 years.
Patients characteristics were globally similar with two
exceptions: histological subtype and tumor size. Signif-
icant differences could be found concerning prognostic
ejc supplements 10, no. 1 (2012) 160166 165
factors between the AYA population and older patients,
and adjuvant chemotherapy was associated with im-
proved RFS only in the older population, highlighting age-
specic differences and prognostic information in this
population.
28
5. Future strategy of the group
Given the recent success of dening diagnostic and
therapeutic targets in sarcoma, like the IGFR1-receptor in
Ewing sarcoma, PDGFR-b in DFSP, or ALK/MET in alveolar
soft-part sarcoma and inammatory myobroblastic
tumors, a major part of the future strategy of STBSG is
intensifying translational research. The EU FP7 funded
networks of excellence Conticanet and EuroBonet were
both headed by group ofcers (J.Y. Blay and P. Hoogen-
dorn) and brought together a framework of research
centers involving several group sites.
The recently founded EUROSARC consortium involves
several group sites and will further develop a network
of sarcoma centers mainly devoted to conducting
studies in rare sarcoma subtypes where funding through
pharmaceutical or biotechnology companies cannot be
expected beyond the supply of drugs. A major grant
has been received from the EU for these efforts in the
eld of rare cancer. Beyond pan-European collaboration,
also translatantic (Sarcoma Alliance for Research through
Collaboration, SARC) as well as transpacic cooperation
is in place via the World Sarcoma Network (WSN)
bringing together high-volume centers to enable trials
for super rare sarcoma subtypes as well as creating
research opportunities at the level of the Connective
Tissue Oncology Society, CTOS.
Multimodality therapy of sarcoma is the mainstay for
successful treatment of advanced tumors. The group
provides educational tools like nomograms, surgical
standards for the reporting of primary sarcoma or
GIST resections but also teaching courses for sarcoma
treatment.
The STBSG was founded by a group of mostly medical
oncologists with the aim of improving the systemic
treatment of sarcomas. It has subsequently evaluated
novel techniques such as hyperthermia and is currently
conducting a large phase III study evaluating the role of
external beam radiation in the neoadjuvant setting prior
to surgical therapy of retroperitoneal sarcomas. The role
of the STBSG in identifying the value of imatinib in the
treatment of GIST and other diseases and more recently
the potential value of an anti-angiogenic tyrosine kinase
inhibitor, pazopanib, is acknowledged worldwide. The
innovative approaches to new drug evaluation and the
insights provided by the database have been hugely
inuential. The group is continuously expanding its
membership in the recognition that in the same way
that the treatment of sarcomas is multidisciplinary,
research must span not only the clinical disciplines
but also related sciences such as genetics, biology, and
biotechnology. Only by attracting basic scientists with
an interest in sarcoma to work with us, will we be
successful in advancing the science and ensuring that
our clinical studies incorporate meaningful translational
research. Recent meetings have demonstrated the
range of scientic expertise within the Group and the
enthusiasm to embrace novel scientic techniques to
improve our understanding of these rare and fascinating
diseases. Given the continuing discovery of new, relevant
targets for sarcoma therapy, one can be optimistic that
treatment will continue to advance and that the STBSG
will continue to play a major role in this important
project.
6. Conict of interest statement
Martine van Glabbeke and Monia Ouali declare no
conicts of interest. Peter Hohenberger has acted as an
advisor to Novartis, Pzer, EISAI and PharmaMar. Ian
Judson has acted as an advisor to Novartis, Pzer and
PharmaMar.
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