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Annals of Oncology 21 (Supplement 7): vii270–vii276, 2010
Histology-driven chemotherapy of soft-tissue sarcoma
Department of Oncology, Lund University and Ska˚nes University Hospital, Lund, Sweden
Soft-tissue sarcomas are rare diseases with >50 subtypes. Surgery is the most important treatment in localized
disease, sometimes combined with radiotherapy. Chemotherapy is used as palliation in advanced disease, sometimes
also with a potential to decrease tumour size and eradicate micro-metastases, making meaningful surgery possible.
The role of chemotherapy as adjuvant treatment in localized disease is not finally settled. Doxorubicin and ifosfamide
are the two drugs with the best established response rates in soft-tissue sarcoma, and a combination of these
drugs has been a ‘gold standard’ for several years. However, there is an emerging knowledge of the biology and
sensitivity to treatment for different histological subtypes. New drugs such as gemcitabine, taxanes and trabectedin
have been explored in several studies, showing promising results. Even if most studies have encompassed many
different subtypes and were limited in size, knowledge related to specific treatment for different subtypes is emerging.
Examples are trabectedin in liposacoma and leiomyosarcoma, and taxanes in angiosarcoma.
Key words: chemotherapy, histological subtypes, soft-tissue sarcoma
treatment. This has led to the observation of different
sensitivities for different drugs or drug combinations between
Soft-tissue sarcomas (STS) are rare diseases encompassing <1%
the more common subtypes. Formal evidence to guide first- or
of all malignancies. More than 50 different histological
second-line treatment in different situations is, however, still
subtypes of STS have been described, most of them very rare.
Knowledge of the biological differences between subtypes, such
as their genetics and natural history, has gradually increasedover the years, and we also now understand more about the
sensitivity to treatment of different subtypes. However, theheterogeneity of the subtypes has rarely been taken into account
The most effective drugs, especially doxorubicin, have shown
when performing clinical trials on treatment for STS. Our
an ability to produce overall response (complete or partial) in
present knowledge is therefore mainly based on uncontrolled
advanced cases in the range of 20–30% , even if additional
phase II studies or retrospective case series.
patients benefit minor responses or stable disease for a shorter
Most STS are localized in the extremities, especially in the
or longer time. With the addition of more drugs, e.g.
legs, or on the trunk, but there are also STS localized in
ifosfamide, in combinations, the overall response seems to be
non-orthopaedic sites, e.g. uterus, retroperitoneum, thorax or
somewhat improved , but the effect on overall survival (OS)
head and neck. The most important treatment for all localized
STS is radical surgery whenever possible. For orthopaedic sites,
In most cases the response is limited in time, but long-term
pre- or postoperative radiotherapy is demonstrated to decrease
survivors after only chemotherapy do exist, as shown in studies
Chemotherapy has been widely used for decades in different
Some histiotypes seem to be totally resistant, at least to the
situations in STS: (i) as palliative treatment in advanced cases;
chemotherapeutic drugs available today, even if immunoactive
(ii) for down-staging, i.e. decreasing size to facilitate radical
drugs such as interferon or modern targeted drugs may have
surgery of the primary tumour, lung metastases or,
an effect in some cases. There is no evidence for the use of
occasionally, metastases in other sites; and (iii) as adjuvant or
chemotherapy in, for example, gastrointestinal stromal tumours
neoadjuvant treatment in high-grade localized disease in
(GISTs) , extraskeletal myxoid chondrosarcoma [7, 8], clear
combination with the local treatment of the primary tumour.
cell sarcoma [9, 10] or alveolar soft part sarcoma .
The most used chemotherapeutic drugs in all these
Rather low sensitivity for chemotherapy is reported for, for
situations, especially during later years, have been doxorubicin
example, epithelioid cell sarcoma, adult fibrosarcoma,
and ifosfamide, but especially in palliative situations many
haemangiopericytoma, and malignant peripheral nerve sheet
other drugs have been tested as second or further lines of
tumour (MPNST), but that does not exclude that some patientswith these variants may show response. This probability mayincrease by using drugs or combinations other than
*Correspondence to: Dr M. Eriksson, Department of Oncology, Lund University and
Ska˚nes University Hospital, Lund, Sweden. E-mail: email@example.com
The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: firstname.lastname@example.org
Intermediate sensitivity for chemotherapy seems to be
that patients with leiomyosarcoma did not benefit from
present for most of the more common types of STS, such as
ifosfamide, with a decreased OS (P = 0.0247). A trend towards
liposarcoma, leiomyosarcoma, synovial sarcoma,
better survival was seen for patients with liver metastases
undifferentiated pleomorphic sarcoma and angiosarcoma.
(P = 0.0712). Regarding response, a decrease was seen for both
Some sarcomas more common in childhood and adolescence
liposarcoma (significant) and leiomyosarcoma
are in most cases clearly sensitive to multiagent combinations
(non-significant), but an increase (non-significant) was
of drugs. This is true for extraskeletal Ewing sarcoma,
demonstrated for synovial sarcoma when ifosfamide was added.
rhabdomyosarcoma of embryonal and alveolar types, and
High-dose ifosfamide (9–12 g/m2) as single treatment may
desmoplastic small round cell tumour; the last of these has,
be effective as second-line treatment, even in patients
nevertheless, a very poor prognosis. This group of tumours will
initially treated with doxorubicin and ifosfamide in lower doses
not be discussed further in this review.
Adjuvant treatment with doxorubicin with or without
ifosfamide has been explored in many randomized studies,most of them small, and the results have been conflicting. In
Many chemotherapeutic drugs have been tested in STS with best
brief, the largest studies, performed by the EORTC soft-tissue
single-agent response of 20–30% demonstrated for
and bone sarcoma group, have been negative [25, 26]. On the
doxorubicin . A dose–response relationship has been
other hand, a large meta-analysis with the last published update
demonstrated, with optimal response rates at dose levels between
including 1953 patients from 18 adjuvant trials demonstrated
75 and 90 mg/m2 . Epirubicin is an antracycline analogue of
that the combination of doxorubicin and ifosfamide gave an
doxorubicin, with supposed lower cardiotoxicity, but high-dose
absolute risk reduction for death of 11% . Furthermore,
epirubicin has not been shown to be a useful alternative to
another meta-analysis including one of the EORTC studies also
standard dose doxorubicin in STS . Another way to reduce
showed a significant benefit for doxorubicin-containing
the potential risk of cardiotoxicity using antracyclines may be
adjuvant treatment for both 5-year disease-free survival (DFS)
the use of pegylated doxorubicin, but since the effect of this
and OS . Thus, it is still unclear whether to treat or not in
preparation seems to be inferior to that of standard doxorubicin
the adjuvant setting. The answer may be to select patients with
 this option may be reserved for patients with pre-existing
identified increased risk for metastatic disease based on
cardiac disease who are otherwise excluded from antracyclines or
biological tumour-related criteria; an option currently being
in specific situations as discussed below.
investigated by the Scandinavian Sarcoma Group.
The only other drug with single-agent activity at the same
magnitude is ifosfamide at doses of 9–11 g/m2 . Even ifcardiac toxicity is absent with this drug, it may pose other
problems such as renal or central nervous system (CNS) toxicity.
Many studies have investigated combination therapies,
Dacarbazine is an old alkylating agent approved for use in STS
including doxorubicin and ifosfamide and/or other drugs, as
in many countries. It has a modest activity as a single agent,
reviewed recently . In this review, three phase III studies
with a response rate of 17% [29, 30], and has mostly been used
were included comparing single-agent doxorubicin [17, 18], or
in multidrug combinations as MAID (mesna, doxorubicin,
doxorubicin + dacarbazin , with combinations including
ifosfamide and dacarbazine) or CyVADIC (cyclofosfamide,
ifosfamide [18, 19] or the related drug cyclofosfamide .
vincristine, doxorubicin and dacarbazine). Its role in this
A meta-analysis of these three studies showed that the
context is not proven, but when single-agent doxorubicin was
combinations including ifosfamide/cyclofosfamide produced
compared with CyVADIC an increased response for the
a significantly increased tumour response rate of 50%
combination was shown, where dacarbazine may have
(P = 0.009), but there was no difference in OS after 1 year
contributed . Dacarbazine has also been used as second- or
(P = 0.76). The toxicity was significantly increased in the
further line therapy with some effect .
combination arm, however. In the choice between alkylating
Temozoloamide is an oral analogue of dacarbazine, mainly
agents, ifosfamide has been shown to be the more effective .
used in brain tumours, which also has been explored in STS
Based on these findings, the combination of doxorubicin and
with somewhat conflicting results. A study from EORTC did
ifosfamide is recommended as standard therapy, especially when
not find a meaningful effect as second-line treatment ,
a good response would increase the possibility of surgery with
whereas other studies have shown some responses and disease
curative intent, or when a good response is considered to benefit
stabilization in leiomyosarcoma especially of uterine origin
the individual patient, e.g. by decreasing disturbing symptoms.
[33–36]. Another possible use for this drug could be in
In other cases, doxorubicin alone is preferred if no other
combination with bevacizumab in haemangiopericytoma/
tumour-specific factors favour the combination. Such a factor
could be the histological subtype as discussed further on.
To explore further factors identifying patients who may
benefit from the addition of ifosfamide in first-line treatment,
a retrospective analysis was recently performed on the large
Gemcitabine is a pyrimidine antimetabolite characterized by
patient series from EORTC-STBSG . In this analysis, the
a favourable toxicity profile and used for several malignancies,
increased response rate but equal OS for regimens containing
such as carcinoma in the pancreas and bladder. Its effect in STS
ifosfamide was confirmed. Predictive factor analysis showed
was initially investigated 10 years ago in several small phase II
studies, showing only modest activity with partial remissions
The potential specific sensitivity for gemcitabine in
(PRs) in single patients, mostly those with leiomyosarcomas
leiomyosarcomas has led to investigations limited to such
[38–40]. A somewhat larger study from the M.D. Anderson
tumours of uterine origin, and very promising results have been
Cancer Center comprised 17 patients with gastrointestinal
achieved both in first-line  and in second-line treatment
(GI) leiomyosarcomas and 39 other STS patients . In the
. Furthermore, an adjuvant phase II study with the same
GI group no responses were found; these cases were probably
combination indicated an improved 2-year PFS superior to
all GISTs. In the other group, however, seven PRs were
observed and, interestingly, among them there were four out of10 leiomyosarcomas. The three remaining PRs occurred in one
angiosarcoma, one malignant fibrous histiocytoma (MFH) and
This family of antimitotic drugs has also been explored in STS,
vincristine as early as in the 1960s. As a single agent its activity
Apart from the verified responses, disease stabilization for
seems to be very limited, with a possible exception for
a shorter period has also been demonstrated in some of these
paediatric rhabdomyosarcoma . Nevertheless, its use in
studies, also confirmed by later reports [42, 43]. One study explored
combinations as CyVADIC was established as a standard in
gemcitabine as first-line therapy in advanced STS with rather
the late 1970s following US studies with very promising
disappointing results; 7% PR and 20% stable disease (SD) .
responses . Later on, the efficacy of vincristine in adult
The promising effect of gemcitabine in some studies,
STS was questioned, and its use has been abandoned.
especially with regard to leiomyosarcomas, has prompted
However, some studies indicate effects in some patients
studies with combinations including this drug. This has led to
treated with other Vinca alkaloids such as vindesine  or
the development of the now very common combination of
vinorelbine . Vinorelbine in combination with
gemcitabine and docetaxel described below.
gemcitabine has been associated with meaningful diseasecontrol, also including one patient with a high-grade
pleomorphic sarcoma achieving a complete remission lasting
Paclitaxel has shown a convincing activity in human
immunodeficiency virus (HIV)-associated Kaposi’s sarcoma[45, 46]. Several reports have also demonstrated that classical
Kaposi’s sarcoma responds to the taxanes docetaxel  or
Binding of the DNA minor groove is the mechanism of action
for the marine-derived drug trabectedin, making it the first
A high response rate for paclitaxel in angiosarcoma of the
compound in a new class of chemotherapeutic drugs.
scalp or face  has shown this treatment to be a reasonable
Intensively explored in many malignant diseases, it was initially
first-line option, and a later study showed that a similar effect is
considered of specific interest in STS based on promising
achieved by docetaxel . Other angiosarcomas also respond
results in phase II studies in pre-treated patients showing rather
well to paclitaxel  or docetaxel [54, 55]. Radiation-induced
low response rates, but stabilization of disease in several
angiosarcomas most often occur in the breast, and in advanced
patients and an OS of 1 year [74–76]. Since a somewhat
cases good treatment options seem to be offered by docetaxel
superior efficacy was indicated for liposarcomas and
leiomyosarcomas in these studies, a randomized multicentre
Paclitaxel has also been explored for other STS with some
phase II study including these histiotypes was performed
activity demonstrated in first-line treatment , but without
comparing two dose schedules: 1.5 mg/m2 in 24 h every third
a clear effect in pre-treated patients [59, 60]. In previously
week and 0.58 mg/m2 in 3 h every week for three weeks out of
treated leiomyosarcoma of the uterus a moderate efficacy has
four. A statistically significant benefit was demonstrated for the
schedule with 24 h infusion every third week, with a mediantime to progression of 3.7 versus 2.3 months, and a median
PFS at 6 months of 35.5% versus 27.5% . Based on these
The combination of gemcitabine and docetaxel, both with
results, trabectedin was approved in Europe as second-line
modest activity in STS, has been investigated in different STS,
and promising effects have been found, especially for
Tumour response has been noted in several different
leiomyosarcoma, but to a certain extent also for other
histological subtypes, but the most marked sensitivity has been
seen in liposarcoma and leiomyosarcoma, followed by synovial
A randomized trial compared single-agent gemcitabine in
sarcoma. Myxoid liposarcoma seems to be especially sensitive
fixed dose with a lower fixed dose gemcitabine combined with
to trabectedin, which recently was verified in a single-
docetaxel . The combination produced better progression-
institution series from Milan with a response rate of 50% and
free survival (PFS) and OS compared with gemcitabine alone.
In the combination arm, response or disease stabilization for at
The combination of trabectedin and doxorubicin has been
least 24 weeks was observed in eight out of 29 patients with
explored in a dose-finding phase I study in 41 patients .
leiomyosarcoma, in seven out of 11 patients with a high-grade
Five patients (12%) achieved a PR (two myxoid liposarcoma,
pleomorphic sarcoma and in two out of 3 patients with
one other liposarcoma, one leiomyosarcoma and one with
pleomorphic liposarcoma, whereas other histiotypes responded
sarcomatoid carcinoma) and 37% maintained stable disease
for >6 months. Median PFS was 9.2 months.
hampered by the rarity of all these variants, and the
The topoisomerase II inhibitor etoposide in short-duration
following recommendations must therefore be interpreted with
infusions has not shown convincing activity in studies in STS,
caution. However, in spite of lacking randomized trials for
either as a single drug  or in combination with ifosfamide
most situations, there is now good reason for not always
[81, 82]. However, a randomized study in small cell lung cancer
using ‘the golden standard’ of doxorubicin 6
has shown a dramatic schedule dependency of this drug,
favouring long-duration continuous infusions . Based on
Certainly, issues other than histology also influence our
that observation, the Scandinavian Sarcoma Group has treated
choice of treatment. Age, co-morbidity and expected tolerance
advanced STS with 600 mg/m2 given continuously for
of side effects may all be of importance, with less toxic
72 h followed by ifosfamide 1.5 g/m2 per day for 3 days,
regimens to be preferred for more vulnerable patients. The
supported by granulocyte colony-stimulating factor (G-CSF);
purpose of the treatment is also of importance, and in patients
both drugs were dose escalated if haematological toxicity so
where surgery with curative intent may be possible later, the
permitted . In spite of a relatively low dose of ifosfamide, an
regimen with best possible response should be used.
overall response of 42% (11% CR, 31% PR) was noted in this
Furthermore, for some patients, options other than
group of untreated patients with metastatic or locally advanced
conventional chemotherapy may be available. Such options
disease. A marked dose–response association was observed.
may be chemotherapy with hyperthermia, showing impressive
The combination of etoposide with carboplatin induced
results in a randomized study , isolated limb perfusion
remissions in one study of MPNST refractory against first-line
[94, 95] or targeted drug therapy. In the following
treatment . Pre-clinical data indicate elevated levels of
recommendations, none of these factors has been taken
topoisomerase IIa in MPNST, and it is possible that etoposide
is especially useful in this histiotype.
The following recommendations only include specific
This concept is further investigated in an ongoing trial of the
options and advice for some of the more common histiotypes,
US group SARC (Sarcoma Alliance for Research through
and do not exclude the use of the other options mentioned
Collaboration). Early results speak in favour of a possible effect
of the combination of ifosfamide and etoposide in MPNST.
Etoposide has also been given in tablet form, but as a single
drug at doses of 50 mg/m2 daily it has shown no or low efficacy
non-uterine. No drug has been shown to be superior to
[86, 87]. In per oral combinations, e.g. with trofosfamide, it
doxorubicin in this common entity, but ifosfamide should
may be more active, as discussed below.
probably be avoided as discussed above . As second line,there are two good alternatives: (i) gemcitabine + docetaxel
[62–65]; and (ii) trabectedin .
Trofosfamide is an oxazaphosphorine with ifosfamide as the
uterine. Gemcitabine + docetaxel seems to be the most effective
main metabolite, and with generally low toxicity. It is given as
option in this entity [86, 87] and may be regarded as first-line
tablets, continuously or over longer periods, so-called
treatment. As further line treatments doxorubicin
metronomic use, which is shown to sharply reduce endothelial
and trabectedin may be used, and temozolomide may also be
progenitor cells that may participate in tumour angiogenesis
. Some phase II studies have shown activity in heavilypre-treated patients with advanced STS, predominantly disease
stabilization but also some formal responses [89–91]. Another
Doxorubicin is regarded as first-line treatment. Whether to add
trial used the drug as maintenance after partial remission or
ifosfamide or not is an open question in the light of the
disease stabilization and seemed to demonstrate a prolonged
recent EORTC survey indicating a somewhat lower response
PFS and OS compared with patients without maintenance .
rate for the combination . Since the main reason to add
An ongoing German randomized phase II trial is comparing
ifosfamide in the treatment of STS in general is the
oral trofosfamide with intravenous doxorubicin in metastatic
possibility of achieving a better response, liposarcoma may be
an entity favourably treated with doxorubicin only, as
Furthermore, the German Cooperative STS study (CWS)
described for leiomyosarcoma. Trabectedin seems to be
recommended trofosfamide as maintenance therapy in
a reasonable second-line choice ; in myxoid liposarcomas
combination with oral etoposide and idarubicin after aggressive
it may even be more effective than doxorubicin for many
chemotherapy in children with STS. The combination of
etoposide and trofosfamide has been used in Scandinavia aspalliation for patients failing single-agent trofosfamide. Results
are often encouraging, but have not yet been published.
Doxorubicin + ifosfamide is strongly recommended for thisentity, which seems to be the histiotype which benefits most
from ifosfamide . The concept of using high-dose ifosfamide
as a single drug even after resistance to the combination,which has been successful in several studies [22–24], may be
The evidence-based knowledge of the optimal
especially well suited for this entity. Some patients with synovial
chemotherapeutic drugs to use in specific STS histiotypes is
sarcoma also seem to benefit from trabectedin [76, 96].
STS, emerging knowledge indicates that other drugs may be
Taxanes (paclitaxel or docetaxel) seem to be the drugs of
defined as the first- or second-line choice for certain
first-line choice [51–57], reserving doxorubicin + ifosfamide for
histiotypes. The most important of these drugs seem to be
trabectedin, gemcitabine and taxanes, but others, such asetoposide, dacarbazine and temozolomide, may play an
important role. Collaborative efforts with preferablyrandomized trials are needed to increase our knowledge of the
Doxorubicin + ifosfamide is the main alternative, assuming that
best available treatment for these rare tumours.
the findings of the superiority of this combination for STS ingeneral is also true for this common entity. If the impressiveeffect of gemcitabine + docetaxel found in one study  is
verified, this could be an alternative.
The author has received honoraria from Novartis, SwedishOrphan, GSK, MSD and Pfizer.
Doxorubicin + ifosfamide is regarded as the standard option
even if this histiotype probably has a rather low sensitivity forthis combination. Ongoing and further studies will define the
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