Retrospective Comparison of the Efficacy of Therapeutic Agents in Metastatic Soft-Tissue Sarcomas

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TURKISH JOURNAL of ONCOLOGY
Retrospective Comparison of the Efficacy of Therapeutic
Agents in Metastatic Soft-Tissue Sarcomas
Received: December 04, 2022
Accepted: February 22, 2023
Online: March 02, 2023
Accessible online at:
www.onkder.org
Turk J Oncol 2023;38(2):238–45
doi: 10.5505/tjo.2023.3884
ORIGINAL ARTICLE
Burcu CANER,1 Brol OCAK,2 Ahmet Blgehan ŞAHİN,3 Seda SALİ,1 Eyüp ÇOBAN,1
Adem DELİGÖNÜL,1 Erdem ÇUBUKÇU,1 Türkkan EVRENSEL1
1Department of Medical Oncology, Bursa Uludağ University Faculty of Medicine, Bursa-Türkiye
2Department of Medical Oncology, Bursa Yüksek İhtisas Training and Research Hospital, Bursa-Türkiye
3Department of Medical Oncology, Uşak University, Uşak-Türkiye
OBJECTIVE
ere are few agents used in so-tissue sarcoma treatment. We compared the ecacy of therapies, aiming to
identify the best therapy sequence, and reveal the factors aecting the risk of progression or death.
METHODS
Fiy-ve patients were included in the study. Data such as age, gender, tumor primary site, histological type,
tumor grade, the Ki67 percentage score, treatments, radiotherapy, and metastasectomy history, the dates
of diagnosis, metastasis, progression, and death were retrospectively evaluated. Progression-free survival
(PFS) and overall survival (OS) for therapies, and the risk factors for the progression or death were analyzed.
RESULTS
In the rst-line, gemcitabine-docetaxel provided longer PFS than the doxorubicin-ifosfamide combina-
tion (7.4 months vs. 4.8 months, p=0.035), although this did not result in OS dierence. In the second-
line, the ecacy of trabectedin and pazopanib were similar, whereas trabectedin showed less activity in
liposarcomas. In the third-line and beyond, trabectedin, pazopanib and eribulin showed similar PFS
and OS. e only factor that aected the risk of death was metastasectomy (HR for death: 0.35, 95% CI:
0.18–0.66, p=0.001).
CONCLUSION
We found that agents used in so-tissue sarcoma have similar ecacy, which is not aected by the
previous therapies. However, it should be noted that so-tissue sarcomas include many histological
types, and to choose the optimal drug, the histological type must be one of the major factors considered.
Furthermore, all patients should be evaluated for possible metastasectomy, which came out as the only
factor reducing the risk of death in our study.
Keywords: Eribulin; pazopanib; sarcoma; trabectedin.
Copyright © 2023, Turkish Society for Radiation Oncology
Dr. Burcu CANER
Bursa Uludağ Üniversitesi Tıp Fakültesi,
Tıbbi Onkoloji Anabilim Dalı,
Bursa-Türkiye
E-mail: drburcucaner@gmail.com
OPEN ACCESS This work is licensed under a Creative Commons
Attribution-NonCommercial 4.0 International License.
INTRODUCTION
So-tissue sarcomas are cancers originating from
mesenchymal cells and contain many histological
types. ese rare tumors make up about 1% of adult
cancers. Sarcomas can occur in any site, such as the
extremities (the most common site), thorax, abdo-
men, and retroperitoneum. While surgery and radio-

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Caner et al.
Retrospective Comparison of the Ecacy of Therapeutic Agents in Metastatic Soft-Tissue Sarcomas
therapy constitute the primary treatment for the ear-
ly-stage disease, for metastatic disease chemotherapy
is the mainstay of treatment. Sarcomas are “immune
cold” tumors. Unlike many other cancers, immuno-
therapy is ineective in the treatment, except only
in a small group with high microsatellite instability,
showing some activity. Conventional chemotherapy is
still the treatment of choice. It has been long known
that sarcomas are anthracycline-sensitive tumors, and
currently, the standard rst-line treatment is doxoru-
bicin monotherapy. Doxorubicin therapy provides a
median of 7–8 months of progression-free survival
(PFS). Aer progression, the treatment options in-
clude pazopanib, trabectedin, eribulin, gemcitabine-
taxane, dacarbazine, and ifosfamide. Many criteria
are evaluated to choose the optimal agent, including
histology. Trabectedin appears to be more eective in
leiomyosarcoma, while eribulin seems more eective
in liposarcoma, and pazopanib is eective in non-
liposarcoma histologies. However, there is no study
comparing these three agents head-to-head.
Sarcomas have a poor prognosis. Despite intensive
treatment, median overall survival (OS) in metastatic
disease is <2 years; at 2–3 years, only 20% of patients
are still alive. Besides new therapy options, optimal se-
quencing of the current agents may contribute to the
patients’ survival. In this retrospective study, we aimed
to evaluate the treatment choices and responses, PFS,
and OS of patients with metastatic so-tissue sarcoma
and determine the aecting factors for death.
MATERIALS AND METHODS
e medical records of patients between January 01,
2010, and May 01, 2022, in the Medical Oncology Clin-
ic were reviewed to identify patients over the age of 18
who received chemotherapy with the diagnosis of so-
tissue sarcoma (excluding GIST, rhabdomyosarcoma,
Ewing sarcoma, desmoids, and dermatobrosarcoma
protuberans, Kaposi sarcoma). Fiy-ve eligible pa-
tients were included in the study. Age, gender, histo-
logical type, pathological grade, Ki67, primary site,
treatments, radiotherapy, and metastasectomy history
were evaluated. Best responses, PFS, and OS times
were determined according to RECIST 1.1 criteria.
e overall response rate (ORR) includes complete re-
sponse (CR) and partial response (PR); and the disease
control rate (DCR) includes CR, PR, and stable disease
(SD). PFS is the time between initiation of therapy and
progression or death; OS is the time between initiation
of therapy and death. Treatment side eects were eval-
uated according to the CTCAE (Common Terminol-
ogy Criteria for Adverse Events) version 5.0.
Treatment regimens were doxorubicin-ifosfamide
(60 mg/m2 on day one, ifosfamide-mesna 2.5 g/m2 per
day IV on 1–3 days in every 3 weeks), gemcitabine-
taxane (gemcitabine 900 mg/m2 on days 1 and 8 plus
docetaxel 75 mg/m2 on day 8 in every 3 weeks), tra-
bectedin (1.5 mg/m2 iv infusion over 24 h through the
central venous access port, in every 3 weeks), pazo-
panib (800 mg daily), and eribulin (1.4 mg/m2 iv on
days 1 and 8 in every 3 weeks). Pazopanib was given to
non-liposarcoma histologies.
Statistical Analysis
Statistical analysis was performed using SPSS 23 sta-
tistical soware. Factors that may be related to death
and progression were evaluated with the logistic re-
gression test, and PFS and OS were evaluated with
the Kaplan–Meier test, with comparisons made with
the log-rank test.
RESULTS
Fiy-ve patients with metastatic so-tissue sarcoma
were included in the study. e median age was 54
(minimum-maximum: 19–79). ere were 31 women
and 24 men. At diagnosis, 21 patients had metastatic
disease, and 34 had early-stage disease. Twenty-nine
patients (52.7%) received adjuvant chemotherapy.
About 50.9% (28 patients) of the whole group received
doxorubicin as adjuvant therapy. e demographic and
clinical characteristics of the patients are listed in Table
1. e distribution of the patients according to the sec-
ond and third-line therapies is given in Table 2.
First-line Treatment
e median PFS of 24 patients receiving doxorubicin-ifos-
famide was 4.8 months (SD 1.41, 95% condence interval
[CI]: 2.10–7.63), of 29 patients receiving gemcitabine-
docetaxel was 7.4 months (SD 0.23, 95% CI: 6.99–7.93,
p=0.035). In the doxorubicin group, the median number
of treatment cycles was 4, and the ratio of patients who re-
ceived six cycles was 34.8%; in the gemcitabine-docetaxel
group, the median number of cycles given was 6, and the
ratio of patients who received six cycles was 69%. Rea-
sons for discontinuation were intolerance in 5 (33.3%),
progression in 10 (66.7%) in the doxorubicin-ifosfamide
group; intolerance in 2 (22.2%); and progression in 7
(77.8%) in the gemcitabine-taxane group.
ere was no dierence in OS between the groups.
e median OS of the doxorubicin-ifosfamide group

Turk J Oncol 2023;38(2):238–45
doi: 10.5505/tjo.2023.3884
240
was 31.7 months (SD 3.93, 95% CI: 24.0–39.4), and
the gemcitabine-docetaxel group was 22.4 months (SD
1.01, 95% CI: 20.4–24.4, p=0.90) (Fig. 1).
Second-line Treatment
Treatment responses were 50% disease control for tra-
bectedin and 66.7% for pazopanib. Median PFS of pa-
zopanib was 7.6 months (SD 3.99, 95% CI: 0.00–15.43),
median PFS of trabectedin was 3.7 months (SD 3.04, 95%
CI: 0.00–9.65, p=0.92). When liposarcoma histologies
were excluded, the median PFS of three patients in the
trabectedin arm was 7.2 months. Trabectedin seemed to
be less eective in liposarcomas than other histologies.
e PFS of the second-line treatments was compared
according to the given rst-line treatment, and no dif-
ference was found between the groups (p=0.49) (Table
3). e median OS was 14.1 months for pazopanib (SD
4.64, 95% CI: 5.05–23.27), and 30.6 months for trabecte-
din (SD 13.68, 95% CI: 3.80–57.46, p=0.15) (Fig. 2).
≥Third-line Treatments
Treatment responses were 55.6% disease control for
trabectedin, and 50% for pazopanib. All ve responses
were progressive disease for eribulin. e median
PFS for pazopanib was 5.8 months (SD 1.70, 95% CI:
2.53–9.19), 2.7 months for trabectedin (SD 0.99, 95%
CI: 0.78–4.68), and 4.2 months for eribulin (SD 1.60,
95% CI: 1.11–7.41). e median OS for pazopanib was
8.5 months (SD 1.16, 95% CI: 6.21–10.78), 5.8 months
for trabectedin (SD 0.99, 95% CI: 5.63–6.02), and 12.3
months for eribulin (SD 3.99, 95% CI: 4.54–20.19).
ere was no dierence in PFS and OS between groups
(p=0.62 and p= 0.95, respectively) (Fig. 3).
Toxicity
When the toxicity of the agents was evaluated, the fre-
quency was 67.6% (all were grade 1 or 2) for pazopanib,
100% (grade 3–4 68.8%) for trabectedin, and 40% (all
grade 1–2) for eribulin. Grade 3–4 side eects were
seen in patients receiving trabectedin; those were cy-
topenias, nausea-vomiting, and elevated liver enzymes.
Treatment-related death was not observed.
OS
e median OS at the metastatic stage was 26.6 months
(SD:4.45, 95% CI: 17.89–35.36) for all patients. In non-L
histologies (other than leiomyosarcoma and liposar-
coma), OS was signicantly worse than L-sarcomas
(median OS 23.4 months versus 26.2 months, p=0.017).
Logistic regression analysis showed no signicant corre-
lation between gender, primary site, ECOG performance
score, histological type, Ki67 value, rst-line treat-
ment regimen, and risk of death. With metastasectomy
(OR:0.18. p=0.56), longer second-line treatment PFS
(OR:0.91. p=0.082), and longer ≥third-line treatment
PFS (OR:0,89. p=0.057), there was a decrease in the risk
of death, but statistical signicance was not reached.
Twenty-three patients (41.8 %) had metastasectomy; all
were pulmonary metastasectomies. In the survival anal-
Table 1 Demographic and clinical characteristics of the
patients
n %
Median age (min-max) 54.7
(19–79)
Sex
Female 31 56.4
Male 24 43.6
Primary site
Uterus 9 16.4
Retroperitoneal 19 34.5
Trunk 4 7.3
Extremity 23 41.8
Adjuvant chemotherapy 29 52.7
Doxorubicin-ifosfamide 28 96.6
Dacarbazine-platinum 1 3.4
ECOG score
0 9 16.4
1 34 61.8
2 12 21.8
Histology
Leiomyosarcoma 22 40
Liposarcoma 10 18.2
Undierentiated pleomorphic sarcoma 7 12.7
Malignant peripheral nerve sheath tumor 6 10.9
Others* 10 18.2
1st line treatment
Doxorubicin-ifosfamide 24 43.6
Gemcitabine-taxane 29 52.7
Dacarbazine 1 1.8
Dacarbazine-platinum 1 1.8
Later line treatments
Trabectedin 17 30.9
2nd line 8 47.1
≥3rd line 9 52.9
Pazopanib 34 61.8
2nd line 18 52.9
≥3rd line 16 47.1
Eribulin (≥3rd line) 5 9.1
Metastasectomy
Yes 23 41.8
No 32 58.2
*: Synovial sarcoma (3), desmoplastic round tumor (2), myxobrosarcoma (2),
brosarcoma (1), pleomorphic malignant brous histiocytoma (1), angiosarco-
ma (1). ECOG score: Eastern Cooperative Oncology Group performance score

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Retrospective Comparison of the Ecacy of Therapeutic Agents in Metastatic Soft-Tissue Sarcomas
ysis, a signicant dierence was found between the OS of
the patients who had and did not have metastasectomy.
e median OS was 51.9 months for the metastasec-
tomy group (SD: 16.59, 95% CI: 19.37–84.42), and 22.4
months for the non-metastasectomy group (SD: 1.63,
95% CI: 19.26–25.67, p=0.003) (Fig. 4). In Cox regres-
sion analysis, the hazard ratio for death was 0.35 for the
metastasectomy group (95% CI: 0.18–0.66, p=0.001).
Table 2 Distribution of patients according to the second and ≥ third-line treatments
Sex-median age ECOG score Histology Metastasectomy
2nd line pazopanib Female: 9 (50%) ECOG 0: 2 (11.1%) Leiomyosarcoma 5 (27.8%) Yes: 6 (33.3%)
Male: 9 (50%) ECOG 1: 12 (66.7%) Undierentiated pleomorphic No: 12 (66.7%)
Median age: 51.6 ECOG 2: 4 (22.2%) sarcoma 5 (27.8%)
(SD: 17.7. 19–79) Others* 8 (44.6%)
2nd line trabectedin Female: 3 (37.5%) ECOG 0: 1 (12.5%) Leiomyosarcoma 3 (37.5%) Yes: 3 (37.5%)
Male: 5 (62.5%) ECOG 1: 4 (50%) Liposarcoma 5 (62.5%) No: 5 (62.5%)
Median age: 58.5 ECOG 2: 3 (37.5%)
(SD:13.2. 37–75)
≥3rd line pazopanib Female: 11 (68.8%) ECOG 0: 2 (12.5%) Leiomyosarcoma 8 (50%) Yes: 4 (25%)
Male: 5 (31.3%) ECOG 1: 8 (50%) Undierentiated pleomorphic No: 12 (75%)
Median age: 57.3 ECOG 2: 6 (37.5%) sarcoma 2 (12.5%)
(SD: 15.2. 25–74) Others **6 (37.8%)
≥3rd line trabectedin Female: 5 (55.6%) ECOG 0: 4 (44.4%) Leiomyosarcoma 5 (55.6%) Yes: 6 (66.7%)
Male: 4 (44.4%) ECOG 1: 5 (55.6%) Liposarcoma 3 (33.3%) No: 3 (33.3%)
Median age: 55.5 Malignant peripheral
(SD: 10.4. 40–72) nerve sheath tumor
1 (11.1%)
≥3rd line eribulin Female: 4 (80%) ECOG 1: 5 (100%) Leiomyosarcoma 2 (40%) Yes: 4 (80%)
Male: 1 (20%) Liposarcoma 2 (40%) No: 1 (20%)
Median age: 55.4 Synovial sarcoma 1 (20%)
(SD: 11.4. 43–69)
*: Synovial sarcoma, desmoplastic round tumor, myxobrosarcoma, brosarcoma, pleomorphic malignant brous histiocytoma, angiosarcoma. ECOG score: Eastern
Cooperative Oncology Group performance score
Fig. 1. PFS and OS graphics of rst-line therapies.
PFS: Progression-free survival; OS: Overall survival.

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242
DISCUSSION
At present, anthracycline is the preferred rst-line
therapy in metastatic so-tissue sarcoma. When doxo-
rubicin is used alone, it provides a 14% response rate.
Although the response rate is increased (26%) when
used in combination with ifosfamide, and there is a
PFS benet, the survival benet of the combination
regimen could not be demonstrated.[1] Moreover, the
higher toxicity of the combination regimen limits its
use. In a study evaluating treatment with doxorubicin
(including patients using it alone or in combination),
median PFS and OS were 8.7 months and 20.1 months,
respectively.[2] A combination regimen could still be
preferred to obtain a better tumor response in pa-
tients with a high tumor burden. Some experts prefer
the gemcitabine-taxane regimen in the rst-line, es-
pecially in uterine leiomyosarcoma. In a retrospective
review, the gemcitabine-docetaxel regimen provided
an ORR of 18% for sarcoma (24% for leiomyosar-
coma). At 12 months 51%, and at 24 months, 15% of
patients were still alive. is suggested that the com-
bination regimen was as eective as doxorubicin.[3]
When single-agent doxorubicin was compared to the
gemcitabine-taxane regimen in the GeDDis trial, no
dierence in PFS or OS was observed, 46% of patients
in both groups were progression-free at 24 weeks,
with doxorubicin being better tolerated. As a result,
the gemcitabine-taxane combination is typically not
employed in the rst-line setting for anthracycline-
sensitive histologies. Still, it could be preferred for pa-
tients not suitable for anthracycline therapy.[4]
While the second and aer-line treatment options
are determined according to many criteria, including
histology, options include ifosfamide, gemcitabine-
taxane, dacarbazine, pazopanib, trabectedin, and
eribulin. In the phase 3 PALETTE study, pazopanib
was compared with placebo as second-line therapy
for histologies other than liposarcoma in patients
who progressed on anthracycline therapy. e pa-
zopanib arm had a signicantly better median PFS
(4.6 vs. 1.6 months) in the study. OS was the same
for both treatment arms (12.5 vs. 10.7 months). ere
was PR in 6%, and SD in 67% of the pazopanib arm.
[5] Trabectedin appears to have activity in leiomyo-
sarcomas and liposarcomas (particularly the round
cell/myxoid subtype), and perhaps other histologies.
In the ET743-SAR-3007 trial, patients with metastatic
leiomyosarcoma or liposarcoma who had progres-
sion aer anthracycline-based chemotherapy were
randomly assigned to trabectedin versus dacarba-
zine. Approximately three-fourths of those enrolled
had leiomyosarcoma, and the remaining one-third
had liposarcomas. In the trial, relative to dacarbazine,
trabectedin demonstrated improved PFS but similar
OS (median PFS 4.2 versus 1.5 months; median OS
13.7 versus 13.1 months).[6,7] Another agent eribu-
lin has the most signicant activity in dedierentiated
or pleomorphic liposarcoma. Eribulin’s ecacy over
dacarbazine in advanced liposarcoma and leiomyo-
sarcoma was observed in a phase III trial, with both
drugs showing similar PR rates ([4%] in the eribu-
lin arm vs. [5%] in the dacarbazine arm) or SD rates
([52%] vs. [48%] in the dacarbazine arm); similar
median PFS: 2.6 months; but the eribulin arm having
signicantly improved OS in comparison with the da-
carbazine arm (median 13.5 months vs. 11.5 months,
hazard ratio 0.77 [95% CI 0.62–0.95]; p=0.0169).[8]
Head-to-head comparisons of these agents are un-
known. In a retrospective study evaluating second-line
gemcitabine-taxane and pazopanib, ORR was better
for the chemotherapy arm (26.7% vs. 6.5%), but OS
was not dierent for the two groups (14.2 months vs.
12.6 months, p=0.362).[9] In a study revealing a real-
life experience from Japan, the DCR at 8 weeks was
58.5%, and the median OS was 12.6 months. ere
was no comparison between the ecacies of therapies.
[10] Another retrospective study evaluating second-
line therapies in synovial sarcoma reported an ORR of
9.4% and a DCR over 6 months of 34.3%. is study
also did not reveal any preference for any agent.[11] An
abstract in ESMO 2017 presented data analyses from
PALETTE and SAR 3007; in a sample size of 372 pa-
Table 3 PFS of second-line treatments stratied according
to the rst-line regimen
1st line 2nd line Median
treatment treatment
95% CI
Estimate Std. Lower
Upper
Error bound
bound
Doxorubicin Pazopanib 5.23 7.40 0.00 19.73
Trabectedin 3.70 0.87 1.98 5.41
Overall 5.23 2.28 0.75 9.71
Gemcitabine- Pazopanib 10.76 4.24 2.44 19.08
taxane Trabectedin 7.20 4.51 0.00 16.05
Overall 10.76 3.15 4.58 16.95
Overall Overall 7.20 3.52 0.28 14.11
*log-rank p=0.49. PFS: Progression-free survival; CI: Condence interval; Std.:
Standard

243
Caner et al.
Retrospective Comparison of the Ecacy of Therapeutic Agents in Metastatic Soft-Tissue Sarcomas
tients with leiomyosarcoma, there was no dierence in
PFS or OS between pazopanib and trabectedin.[12] A
study evaluating immune-related markers as a poten-
tial indicator of response to pazopanib, trabectedin, and
eribulin in so-tissue sarcoma showed PFS and OS of
the three agents did not dier. In this study, in the low
neutrophil-to-lymphocyte ratio group, pazopanib had
statistically signicant shorter OS; in the low platelet-
to-lymphocyte ratio group, pazopanib was associated
with shorter OS, and eribulin was associated with lon-
ger OS. PFS was the same in all immune-related marker
subgroups.[13] A study from Japan comparing trabect-
edin and eribulin aer pazopanib therapy showed that
trabectedin had a median OS of 9.1 months and eribu-
lin had 13.8 months. e researchers did not observe
any dierence between agents in terms of OS.[14]
Fig. 2. PFS and OS graphics of second-line therapies.
PFS: Progression-free survival; OS: Overall survival.
Fig. 3. PFS and OS graphics of ≥ third-line therapies.
PFS: Progression-free survival; OS: Overall survival.

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doi: 10.5505/tjo.2023.3884
244
In our study, unlike the GeDDis study, the median
PFS of gemcitabine-taxane as rst-line was found to
be longer. Still, OS was not dierent between the treat-
ment groups. It could be due to the lower median num-
ber of cycles in the doxorubicin group. Furthermore,
malign peripheral nerve sheath tumors are considered
chemoresistant and have a poor response to therapies.
Six patients in our study, all treated with doxorubi-
cin in rst-line, may be the reason for shorter PFS in
this group. Treatment intolerance was higher in the
doxorubicin-ifosfamide group than in the gemcitabine
docetaxel group as expected. ere was no dierence
between the ecacy of the following therapies, accord-
ing to the given rst-line treatment. When trabectedin
and pazopanib in the second-line and trabectedin,
pazopanib, and eribulin in the latter lines were com-
pared, no dierence in response rates, PFS, and OS was
found between the treatment groups. When side eects
were evaluated, pazopanib seemed to be better toler-
ated than trabectedin in our study. Besides L-histology
(liposarcoma or leiomyosarcoma), the only variable
that was shown to aect OS time was metastasectomy.
Pulmonary metastasectomy has long been known to
provide a survival benet in so-tissue sarcomas. In
a meta-analysis published in 2012, the 5-year OS rate
was 25% in patients with pulmonary metastasectomy.
[15] In another study, the median OS of 45.3 months
was reported in the metastasectomy group.[16] Simi-
larly, in our study, the median OS of 51.9 months was
reached in this group. Even in the presence of multiple
metastases, metastasectomy can be performed safely
and should be preferred.[17]
Limitations of the Study
e limitations of our study are the small number of sub-
jects in groups, the variety between the groups in terms
of histological types, and the retrospective nature of the
study. Sarcomas are a heterogeneous group comprising
approximately 70 histological types, and we recognize
that combining all these histologies in one basket is not
optimal. However, the rarity of the disease makes it chal-
lenging to design an ideal trial. Furthermore, the number
of metastatic sites is not reported. One possible reason
for the prolonged survival achieved in the metastasec-
tomy group could be lesser tumor burden in this group.
CONCLUSION
Various agents are used in the treatment of so-tissue
sarcomas and there is no randomized controlled trial
comparing those therapies head-to-head. We retro-
spectively analyzed that our patients’ data and found
all three drugs (trabectedin, pazopanib, and eribulin)
showed similar ecacy. We think that prospective
studies will contribute to answering questions such
as what is the optimal therapy sequence and whether
there is a predictive biomarker to choose the proper
drug. Not surprisingly, we found metastasectomy as the
only factor reducing the risk of death, consistent with
the literature. Surgical resection of metastases as much
as possible and eective chemotherapies undoubtedly
prolongs the survival of sarcoma patients.
Peer-review: Externally peer-reviewed.
Conict of Interest: All authors declared no conict of in-
terest.
Ethics Committee Approval: e study was approved by
the Bursa Uludağ University Faculty of Medicine Clinical Re-
search Ethics Committee (no: 2022-16/51, date: 08/11/2022).
Financial Support: None declared.
Authorship contributions: Concept – B.C., B.O., A.B.Ş.,
S.S., E.Ç., E.Çu., A.D.; Design – B.C., S.S., E.Ç., B.O.,
A.B.Ş., E.Çu., A.D., T.E.; Supervision – E.Çu., A.D., T.E.;
Funding – B.C., S.S., E.Ç.; Materials – B.C., S.S., E.Ç., B.O.,
A.B.Ş.; Data collection and/or processing – B.C., S.S., E.Ç.,
B.O., A.B.Ş.; Data analysis and/or interpretation – B.C.,
S.S., E.Ç., B.O., A.B.Ş., A.D., E.Çu.; Literature search –
B.C., S.S., E.Ç., B.O., A.B.Ş., A.D., E.Çu.; Writing – B.C.,
S.S., E.Ç., A.D., E.Çu.; Critical review – E.Çu., A.D., T.E.
Fig. 4. OS graphic for metastasectomy versus non-me-
tastasectomy groups.
OS: Overall survival.

245
Caner et al.
Retrospective Comparison of the Ecacy of Therapeutic Agents in Metastatic Soft-Tissue Sarcomas
REFERENCES
1. Judson I, Verweij J, Gelderblom H, Hartmann JT,
Schöski P, Blay JY, et al. Doxorubicin alone versus
intensied doxorubicin plus ifosfamide for rst-line
treatment of advanced or metastatic so-tissue sar-
coma: a randomized controlled phase 3 trial. Lancet
Oncol 2014;15(4):415–23.
2. Verschoor AJ, Litière S, Marréaud S, Judson I, Toul-
monde M, Wardelmann E, et al. Survival of so tis-
sue sarcoma patients aer completing six cycles of
rst-line anthracycline containing treatment: an
EORTC-STBSG database study. Clin Sarcoma Res
2020;10(1):18.
3. Bay JO, Ray-Coquard I, Fayette J, Leyvraz S, Cherix S,
Piperno-Neumann S, et al. Docetaxel and gemcitabine
combination in 133 advanced so-tissue sarcomas: a
retrospective analysis. Int J Cancer 2006;119(3):706–11.
4. Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ,
Cowie F, et al. Gemcitabine and docetaxel versus dox-
orubicin as rst-line treatment in previously untreated
advanced unresectable or metastatic so-tissue sarco-
mas (GeDDiS): a randomised controlled phase 3 trial.
Lancet Oncol 2017;18(10):1397–410.
5. van der Graaf WTA, Blay JY, Chawla SP, Kim DW, Bui-
Nguyen B, Casali PG, et al. Pazopanib for metastatic
so-tissue sarcoma (PALETTE): a randomised, dou-
ble-blind, placebo-controlled phase 3 trial. Lancet
2012;379(9829):1879–86.
6. Patel S, von Mehren M, Reed DR, Kaiser P, Charlson
J, Ryan CW, et al. Overall survival and histology-spe-
cic subgroup analyses from a phase 3, randomized
controlled study of trabectedin or dacarbazine in pa-
tients with advanced liposarcoma or leiomyosarcoma.
Cancer 2019;125(15):2610–20.
7. Demetri GD, von Mehren M, Jones RL, Hensley ML,
Schuetze SM, Staddon A, et al. Ecacy and safety of
trabectedin or dacarbazine for metastatic liposar-
coma or leiomyosarcoma aer failure of conventional
chemotherapy: results of a phase III randomized mul-
ticenter clinical trial. JCO 2016;34(8):786–93.
8. S chöski P, Chawla S, Maki RG, Italiano A, Gelderblom
H, Choy E, et al. Eribulin versus dacarbazine in previ-
ously treated patients with advanced liposarcoma or
leiomyosarcoma: a randomised, open-label, multicen-
tre, phase 3 trial. Lancet 2016;387(10028):1629–37.
9. Kim JH, Park HS, Heo SJ, Kim SK, Han JW, Shin
KH, et al. Dierences in the ecacies of pazopanib
and gemcitabine/docetaxel as second-line treat-
ments for metastatic so tissue sarcoma. Oncology
2019;96(2):59–69.
10. Nakamura T, Asanuma K, Hagi T, Sudo A. Clinical
outcome of systemic treatment for advanced so tis-
sue sarcoma: real-life perspective in Japan. DDDT
2020;14:4215–20.
11. Kojima Y, Shimoi T, Seo T, Yazaki S, Okuya T, Ohtake
Y, et al. Poor treatment outcomes with second-line
chemotherapy in advanced synovial sarcoma. OCL
2022;100(7):370–5.
12. Jones RL, Blay JY, Lecesne A, Martin-Broto J, Pontes
MJ, Fernandez Santos JM, et al. A matching-adjusted
indirect comparison of trabectedin and pazopanib for
the treatment of advanced, metastatic, leiomyosarco-
mas. Ann Oncol 2017;28:v524–5.
13. Shimada E, Endo M, Matsumoto Y, Tsuchihashi K,
Ito M, Kusaba H, et al. Does the use of peripheral ım-
mune-related markers ındicate whether to administer
pazopanib, trabectedin, or eribulin to advanced so
tissue sarcoma patients? J Clin Med 2021;10(21):4972.
14. Narahara H, Morimoto M, Tanaka E, Ueda S, Ya-
sunaga Y, Inui Y, et al. Clinical benets of later line
trabectedin and eribulin treatment for so tissue sar-
coma (STS) aer pazopanib treatment from the Nishi-
nomiya Sarcoma Cohort Study (NSCS). Ann Oncol
2018;29:ix126.
15. Treasure T, Fiorentino F, Scarci M, Møller H, Utley M.
Pulmonary metastasectomy for sarcoma: a systematic
review of reported outcomes in the context of ames
Cancer Registry data. BMJ Open 2012;2(5):e001736.
16. Schur S, Hoetzenecker K, Lamm W, Koestler WJ, Lang
G, Amann G, et al. Pulmonary metastasectomy for so
tissue sarcoma--report from a dual institution experi-
ence at the Medical University of Vienna. Eur J Cancer
2014;50(13):2289–97.
17. Gafencu DA, Welter S, Cheufou DH, Ploenes T, Stama-
tis G, Stuschke M, et al. Pulmonary metastasectomy
for sarcoma—Essen experience. J orac Dis 2017;9
(Suppl 12):S1278–81.