Review Article
Metastatic Soft Tissue Sarcomas: A Review of Treatments and New Pharmacotherapies
Mahesh Seetharam*, Kantha R Kolla and Sant P Chawla
Division of Hematology/Oncology, Mayo Clinic, USA
*Corresponding author: Mahesh Seetharam, Division of Hematology/Oncology, Mayo Clinic, Phoenix, Arizona, USA
Published: 08 Mar, 2018
Cite this article as: Seetharam M, Kolla KR, Chawla SP.
Metastatic Soft Tissue Sarcomas:
A Review of Treatments and New
Pharmacotherapies. Clin Oncol. 2018;
3: 1426.
Abstract
Soft Tissue Sarcomas (STS) are a heterogeneous group of rare tumors which arise from mesenchymal cells. The malignant precursor cells may differentiate into several lineages such as muscle, adipose, fibrous, cartilage, nerve or vascular tissue to name a few. There are over 50 different subtypes of soft tissue sarcomas, of which undifferentiated pleomorphic sarcoma, adipocytic sarcoma, leiomyosarcoma, nerve sheath sarcoma being more common. The treatment options for soft tissue sarcoma include surgery, radiation therapy, chemotherapy and targeted therapy. In this article we focus on approved treatments and newer therapeutic approaches for management of soft tissue sarcomas.
Introduction
Soft Tissue Sarcomas (STS) are mesenchymal neoplasms with over 50 subtypes (Figure 1), which vary in molecular, histological and clinical characteristics. They can occur in any site within the body, with extremity, trunk, head and neck, and retroperitoneum being the most common sites. The most common subtypes are Undifferentiated Pleomorphic Sarcoma (UPS), Liposarcoma (LPS), Leiomyosarcoma (LMS), Synovial Sarcoma(SS), and Malignant Peripheral Nerve Sheath Tumors (MPNSTs). Incidence of STSs is rare, with occurrence rate of <1% of adult cancers [1]. Metastasis is common, with up to 50% high grade STSs developing metastases and often die of their disease [2]. TNM staging of soft tissue sarcoma is shown in Table 1. STS is one of the 5 most common causes of cancer related death in young adults and pediatric patient population [1]. Historically, the median Overall Survival (OS) for advanced metastatic STS is about 12 months, whereas the more recent studies with newer drugs have shown overall survival improving up to 18 months. Thus, improvements in treatment modalities are further required [3]. In this article we review treatment options for some of the common and uncommon subtypes of soft tissue sarcomas.
General Treatment Approach of Metastatic Soft Tissue Sarcoma
The most common route of spread of soft tissue sarcomas is hematogenous, mostly to lungs
[4]. Lymph node metastasis is uncommon except with epithelioid sarcomas, rhabdomyosarcomas,
angiosarcomas and clear cell sarcomas [5]. Treatment of metastatic STS is challenging, and the
treatment is mostly palliative with median OS of 12 months to 18 months. Chemotherapy is the
standard approach, and sometimes combined with surgical resection (metastatectomy), with
reported survival benefit [6].
Systemic management
First line chemotherapeutic agents:
a. Doxorubicin +/- Ifosfamide: A randomized phase III trial in 326 patients with advanced
soft tissue sarcoma compared Doxorubicin (doxo) versus with two different treatment schedules
of ifosfamide (continuous IV infusion vs. bolus ifosfamide). Results showed no difference between
the three arms. The progression free survival was 2.52 months (doxo group) versus 2.16 months
(ifosfamide group) and overall survival of 12 months (in doxo group) versus 10.92 months
(ifosfamide group) (p =0.076) [7].
The phase III EORTC 62012 trial compared doxorubicin versus doxorubicin with ifosfamide.
The results showed higher response rate and progression free survival with the combination but no
statistically significant improvement in overall survival (PFS: 7.4 months (doxo + ifosfamide) and
4.6 months (doxo alone group) p =0.003); overall survival: 14.3 months (doxo + ifosfamide) versus
12.8 months (doxo alone) p =0.076). The one year overall survival was numerically higher with
combination but not significant. The combination therapy had higher grade 4 toxicities. Thus, based
on the results, the combination of DOX-IFO still remains a standard
treatment option in patients who are in need for a response prior to
potential surgical resection or with symptomatic metastatic disease
[8].
b. Doxorubicin +/- Olaratumab: Based on phase II data,
olaratumab obtained conditional approval from FDA and EMA in
combination with doxorubicin for patients with metastatic soft tissue
sarcoma in late 2016. The phase II study compared the combination
against doxorubicin single agent as first line treatment for metastatic
soft tissue sarcoma. The median OS (Overall Survival) was 26.5 months
with combination versus 14.7 months with doxorubicin alone (HR
0.46, p =0.0003). The PFS was 6.6 months with combination versus
4.1 months with doxorubicin alone (HR 0.67, p =0.0615). Although
confirmatory phase III data is pending, olaratumab is still considered
an optional agent, but nevertheless promising [9].
c. Gemcitabine +/- Docetaxel: In randomized phase II trials,
Docetaxel in combination with gemcitabine has demonstrated activity,
especially in uterine leiomyosarcoma compared to gemcitabine alone.
The response rate was 16 vs. 8%, with median PFS 6.2 months vs. 3
months and median OS of 17.9 months vs. 11.5 months in Docetaxel
+ gemcitabine versus gemcitabine groups respectively [10].
d. Doxorubicin vs. Docetaxel/Gemcitabine: In the randomized
phase III trial, doxorubicin was studied against combination of
gemcitabine and docetaxel in first line treatment of advanced
unresectable or metastatic soft tissue sarcoma. The results showed no
significant difference in proportion of patients alive and progression
free at 24 weeks between both the groups [46.3% (95% CI 37.5 - 54.6)
vs. 46.4% (37.5 - 54.8)]; median progression free survival was 23.3
weeks in doxorubicin group (95% CI 19.6 - 30.4) vs. 23.7 weeks in
gemcitabine and docetaxel group (95% CI 18.1 - 20.0) (hazard ratio
for PFS was 1.28, 95% CI 0.99 - 1.65, p =0.06) [11].
Second line and beyond systemic therapies:
a. Trabectedin: Trabectedin, an alkylating agent derived from
Caribbean Sea squirt was approved by the FDA in 2015 for metastatic
liposarcoma and leiomyosarcoma (L-sarcomas). The phase III trial
of trabectedin versus dacarbazine showed median progression
free survival of 4.2 months with trabectedin, and 1.5 months with
dacarbazine, Clinical Benefit Rate (CBR) was 34% (trabectedin
group) versus 19% (dacarbazine). The median overall survival was
12.4 months (trabectedin group) versus 12.9 months (dacarbazine
group) (HR 0.87, p =0.37) [12].
b. Pazopanib: Based on results from phase III (PALETTE) trial,
pazopanib, an oral tyrosine kinase inhibitor was approved for nonadipocytic
sarcomas. The study compared pazopanib vs. placebo in
patients who had progressed on anthracycline based regimen. The
results showed a median PFS of 4.2 versus 1.5 months, and disease
stabilization of 67 versus 38% favoring pazopanib in patients with
non-adipocytic sarcomas progressing after first line chemotherapy.
Overall survival was 12.5 months (pazopanib group) versus 10.7
months (placebo group) (p =0.25) [13].
c. Dacarbazine +/- Gemcitabine: In a randomized phase II trial,
combination of Gemcitabine and Dacarbazine every 14 days versus
dacarbazine alone showed improved median PFS (4.2 months versus
2 months) and overall survival (16.8 months versus 8.2 months),
especially in leiomyosarcoma [14].
d. Gemcitabine +/- Docetaxel: In randomized phase II trials,
docetaxel in combination with gemcitabine showed activity in uterine
leiomyosarcoma compared to gemcitabine alone. The RR was 16 vs.
8% favoring the combination, with median PFS of 6.2 months vs. 3
months and OS of 17.9 months vs.11.5 months favoring docetaxel +
gemcitabine [10].
e. Doxorubucin vs. Gemcitabine/Docetaxel: In the randomized
phase III trial, frontline doxorubicin versus gemcitabine and docetaxel
was compared in patients with advanced unresectable or metastatic
soft tissue sarcoma. Results showed no significant difference in
proportion of patients alive and progression free at 24 weeks between
both the groups (46.3% (95% CI 37.5 - 54.6) vs. 46.4% (37.5 - 54.8));
median progression free survival was 23.3 weeks (doxorubicin group)
(95% CI 19.6 - 30.4) vs. 23.7 weeks (gemcitabine and docetaxel) (18.1
- 20.0) (hazard ratio for PFS was 1.28, 95% CI 0.99 - 1.65, p =0.06)
[11].
f. Aldoxorubicin vs. Doxorubicin: A phase 2b, open randomized
study was conducted to evaluate efficacy and safety of Aldoxorubicin
(ALDOX) compared to doxorubicin in patients with advanced soft
tissue sarcomas. Results showed that single agent aldoxorubicin
therapy demonstrated improvement in progression free survival
(5.6 months in ALDOX group Vs 2.7 months in doxorubicin group)
and six months progression free survival (46% and 23% in ALDOX
and doxorubicin groups respectively). ALDOX therapy exhibited
manageable adverse effects and no evidence of acute cardiotoxicity
[15].
g. Aldoxorubicin vs. Investigators’ choice treatment: A
phase III open-label study was conducted to compare safety of
Aldoxorubicin (A) to Investigators Choice (IC) of treatment
(dacarbazine, doxorubicin, pazopanib, ifosfamide, and gemcitabine/
docetaxel) in Soft Tissue Sarcoma (STS) patients, who have relapsed
or were refractory to prior chemotherapy. Results (summarized in
Table 2), found that aldoxorubicin showed Progression Free Survival
(PFS) benefit only in L-sarcoma (liposarcoma + leiomyosarcoma)
and is well tolerated with lack of cardiotoxicity [16].
Role of immunotherapy
NY-ESO-1 is highly expressed in MRC-LPS (myxoid round
cell liposarcoma) and 80% of SS, and also in other subtypes such as
uterine LMS and osteosarcoma [17]. Based on this, a pilot study was
conducted with anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4)
antibody ipilimumab, in NY-ESO-1 expressing SS. Results showed
that ipilimumab was well tolerated with no serious adverse events,
even though no objective responses were seen among the six patients
treated [18]. In another study which was conducted using NY-ESO-1
engineered T cells, four out of six responses were seen in NY-ESOexpressing
SS patients [19].
Tumor-Infiltrating Lymphocytes (TILs) which play an important
role in the immune response, has been found in multiple STS
subtypes such as LPS, LMS, SS and MPNST. Similar to CTLA-4,
the Programmed Cell Death 1 (PD-1) receptor and its Programmed
Death Ligand-1 (PDL-1) is another checkpoint molecule. In a
retrospective study conducted on STS patients, PD-L 1 expression
was found in 100% of patients with epithelioid sarcoma, 53% of SS,
38% of rhabdomyosarcoma, 33% of Ewing sarcoma [20]. A phase II,
SARC 028 trial was conducted in patients with 7 different subtypes
of pretreated sarcomas to evaluate the effect of Pembrolizumab
(Keytruda), PD-1 inhibitor. Treatment with Pembrolizumab resulted
in reduction of tumor size in 33% of patients having undifferentiated
pleomorphic sarcoma and dedifferentiated liposarcoma [21].
Figure 1
Table 1
Specific Soft Tissue Sarcoma Subtypes with Unique Treatment Options
Liposarcoma
Liposarcoma is one of the most common soft tissue sarcomas
which account for nearly 20% of all adult sarcomas. Based on histology
and molecular profile, liposarcomas can be classified into following
categories: well/differentiated liposarcoma/atypical lipomatous
tumor; dedifferentiated liposarcoma; myxoid liposarcoma;
pleomorphic liposarcoma; and liposarcoma, not otherwise specified
[22,23] (Table 3,4,5). Due to their heterogeneity and distinct
underlying molecular mechanisms that drive growth, liposarcoma
subtypes respond variedly to different treatments.
Well-differentiated liposarcoma/Atypical lipomatous tumor:
Well differentiated liposarcoma is the least aggressive among
liposarcoma subtypes which accounts for one-third of liposarcomas
[24]. Surgery is the main treatment of choice [25,26].
Dedifferentiated liposarcoma: Dedifferentiated liposarcoma
has a distant recurrence rate of nearly 30% [27]. Surgical resection
is the main treatment modality. Even with aggressive resection,
some patients have high rates of local recurrence, but standard
chemotherapy regimens are generally ineffective. New treatments
regimens using trabectedin or eribulin could be considered in patients
with unresectable dedifferentiated or advanced liposarcoma [28].
In a phase II randomized clinical trial, patients with well
differentiated/dedifferentiated liposarcoma were treated with
palbociclib. The progression free survival at 12 weeks was 57.2 %
(95% CI) and the median progression free survival was 17.9 weeks
(95% CI). Neutropenia was the most common side effect [29].
Myxoid liposarcoma: Surgery with or without radiation therapy
is the common treatment modality. Approximately 40 % of patients
experience relapse despite local therapy, and chemotherapy using
doxorubicin +/- ifosfamide is a treatment, with reported response
rates of just over 40% [30].
In a retrospective study, patients with myxoid liposarcoma
treated with trabectedin had a response rate of 50 % (CI 95%) and
median progression free survival of 17 months (95% CI) [31].
Other agents in liposarcoma management
CDK4 antagonists: In well differentiated and dedifferentiated
liposarcoma, CDK4 (Cyclin Dependent Kinase 4) is highly expressed,
which makes it an attractive target. In-vitro studies with Palbociclib,
a CDK4/CDK6 inhibitor induced cell cycle arrest at G1 phase in
CDK4 overexpressing liposarcoma cells [32]. A phase II study
with palbociclib 125 mg daily for 21 of 28 days in patients with
well differentiated and dedifferentiated liposarcomas with CDK4
amplification showed 12-week PFS rate of 66% and low incidence of
hematologic adverse events [33].
MDM2 (Murine Double Minute 2 homolog) antagonists:
Increased expression of MDM2 has been observed in dedifferentiated
liposarcoma. Nutlins, a class of midazoline compounds showed
potent activity against MDM2 [34]. A phase I study was conducted
in 68 patients with solid malignancies of which 21 patients with
dedifferentiated liposarcoma were treated with a maximum tolerable
dose of 300 mg/orally/day of SAR405838, an oral spirooxindole
derivative that binds MDM2 with high specificity. Results showed
stable disease in 11 of 21 patients (52%). Most common adverse
events were nausea, fatigue, diarrhoea and thrombocytopenia.
Eribulin: Eribulin is a synthetic macrocyclic ketone derived from
marine sponges, which exerts chemotherapeutic effects through
unique microtubule dynamics inhibitory effect. In a phase III study,
patients with liposarcoma or leiomyosarcoma were randomly
assigned to eribulin or dacarbazine. The primary end point was overall
survival. Results found that patients in eribulin group had overall
survival of 13.5 months compared to 11.5 months in dacarbazine
group. Subset analysis of patients with liposarcoma showed that
patients in eribulin group lived for 15.6 months compared to 8.4
months in dacarbazine group. Due to the significant improvement
of 7.2 months, eribulin was approved for the treatment of inoperable
and advanced liposarcoma on January, 2016 [35].
Liposarcoma subtype specific management options are shown in
Table 6.
Uterine leiomyosarcoma
Leiomyosarcoma accounts for 20% to 25% of STS and may arise
from uterus, retroperitoneum and extremities. Uterine sarcomas
account for approximately 3% to 7% of uterine cancers. The common
subtypes include: 1) Leiomyosarcoma, 2) Endometrial stromal
sarcoma, 3) Adenosarcoma, 4) High Grade Undifferentiated Sarcoma
(HGUS).
In a phase II study patients with advanced or recurrent
leiomyosarcoma received ifosfamide with MESNA (Mercaptoethane
Sodium Sulfonate). Results showed partial response in 17.2% patients
and grade 3 or 4 granulocytopenia in 11% patients [36].
In another phase II study, patients with advanced, persistent or
recurrent uterine leiomyosarcoma were treated with trabectedin.
Results showed partial response in 10% patients; stable disease in 50%
patients; progression free survival and overall survival of 5.8 months
and 26.1 months respectively. Side effects such as neutropenia,
thrombocytopenia and anemia were commonly noted [37].
In another phase 2 study, patients with uterine leiomyosarcoma
positive for Estrogen Receptor (ER) and Progesterone Receptor (PR)
were treated with aromatase inhibitor letrozole. Progression free
survival at 12 weeks was 50% and stable disease was found in 54%
patients [38].
Gastrointestinal stromal tumors
GIST (Gastrointestinal Stromal Tumors) is a form of soft tissue
sarcoma of the gastrointestinal tract. Various mutations have been
identified including in KIT gene (exons 9, 11, 13 and 17), PDGFRA
(Platelet Derived Growth Factor Receptor Alpha) gene (exons 12,
14 and 18). About 10% to 15% of gastrointestinal stromal tumors
carries wild type sequences in all hot spots of KIT and PDGFRA and
hence called as wild type GISTs. The Carney-Stratakis syndrome
comprising of hereditary GIST and paraganglioma is a result of germ
line mutation in the mitochondrial tumor suppressor gene pathway
involving the Succinate Dehydrogenase (SDH) subunits SDHD,
SDHC and SDHB.
The treatment of GI stromal tumors may include combination of
surgery with or without systemic therapy, either in neo-adjuvant or
adjuvant setting. The decision regarding need for systemic therapy is
based on the risk stratification for recurrence. Three tyrosine kinase
inhibitors have been approved for treatment including Imatinib,
Sunitinib and Regorafenib.
Retroperitoneal sarcoma
Retroperitoneal Sarcomas (RPSs) are rare tumors that account
for nearly 15% of STSs [39]. The most common histologic subtypes
are Well or Dedifferentiated Liposarcoma (WDLPS or DDLPS),
leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic
sarcoma and malignant peripheral nerve sheath tumors [40]. The
most common treatment for RPSs is primary resection.
A retrospective analysis to evaluate the effect of adjuvant
radiotherapy found 3 year local recurrence rate was 49% in surgery
alone group and 34% in surgery plus radiotherapy group. However
limited data is available about role of adjuvant chemotherapy in the
management of RPSs [41].
In a prospective trial patients with surgically resected sarcomas of
the retroperitoneum were randomly assigned to receive post-operative
high dose radiotherapy alone or Intraoperative Radiotherapy
(IORT) in combination with low dose post-operative external beam
radiotherapy. Results showed comparable median survival time in
both groups (45 vs. 52 months). In patients who received IORT, there
was lower incidence of loco-regional recurrences (6 of 15 (40%) vs.
16 of 20 (80%)), fewer complications of disabling enteritis (2 of 15
vs. 10 of 20) but a higher frequency of radiation related peripheral
neuropathy (9 of 15 Vs 1 of 20) [42].
In a case control, propensity score matched analysis; overall
survival was assessed in patients with retroperitoneal sarcomas who
received preoperative radiotherapy, postoperative radiotherapy and
no radiotherapy. Results showed overall survival of 110 months in
preoperative group versus 66 months in patients who did not receive
radiotherapy (p <0.0001, 95% CI) and 89 months in postoperative
group versus 64 months in patients without radiotherapy (p <0.0001,
95% CI) [43].
Angiosarcoma
Angiosarcomas are unusual malignant tumors of endothelial
origin with high propensity for metastatic disease and in general with
poor prognosis.
For localized tumors, radical surgical resection is the primary
treatment option. Because of the high risk of local recurrence,
adjuvant radiotherapy +/- chemotherapy is recommended.
In a retrospective study, 9 patients with cutaneous angiosarcoma
received docetaxel. 2/9 patients showed complete response and
4/9 patients showed partial response. 3/9 patients experienced
severe dermatitis; with no significant incidence of neutropenia and
peripheral neuropathy [44].
In a phase II trial, patients with metastatic or unresectable
angiosarcoma were treated with paclitaxel. Results showed
progression free survival of 74% and 45% after 2 and 4 months
respectively. Median time to progression was 4 months and median
overall survival was 8 months. Anemia and fatigue were the most
toxicity [45].
In another phase II trial, 32 patients with advanced angiosarcoma
were treated with bevacizumab. Two patients had partial response; 11
with stable disease and meantime to progression were 26 weeks. One
patient had graded 4 adverse events [46].
Kaposi sarcoma
Kaposi Sarcoma (KS) is an angioproliferative malignancy that
occurs most often due to infection with Human Herpes Virus 8
(HHV-8) and classified into 4 types: Classic; endemic; iatrogenic;
AIDS associated [47].
Management: In a prospective clinical trial, topical Imiquimod
showed objective response (complete or partial) in 47 % patients [48].
Data from case series showed regression of cutaneous Kaposi
sarcoma lesions with topical timolol [49].
Nitrogen cryotherapy and laser therapy have been used for local
control of small CKS (Classic Kaposi’s Sarcoma) lesions [50].
Intralesional therapy: Intralesional injection using
chemotherapeutic agents (commonly vinblastine, bleomycin)
causes local regression of cutaneous KS lesions [51]. Intralesional
injection using Interferon Alfa (IFNa), alone or in combination with
interleukin-2, has also shown regression of CKS lesions [52].
Electrochemotherapy using small electric current (electroporation,
a form of electromotive drug administration) enhances drug delivery
into the tumor. This has been mostly used with bleomycin. In a study
conducted on 23 patients with CKS treated using this approach,
results showed tumor regression in all patients with complete
regression seen in 65% [53].
A prospective study was conducted in 21 HIV infected subjects
(with associated Kaposi sarcoma) to evaluate the effect of Highly
Active Antiretroviral Therapy (HAART) on circulating Kaposi
Sarcoma (KS) associated Herpes Virus (KSHV) load in HIV infected
individuals. 10/21 patients showed favorable Kaposi sarcoma response
(Complete response: 6; partial response: 4) with HAART alone.
60% of patients had an undetectable KSHV load with antiretroviral
therapy. No significant difference between subjects receiving protease
inhibitors or non-nucleotide reverse transcriptase inhibitor based
treatment combination was noticed [54].
In a retrospective study pretreated patients with aggressive,
non-visceral classic Kaposi sarcoma received pegylated liposomal
doxorubicin. Complete and partial responses were noticed in 10% and
70 % of patient population. 20% of patients developed neutropenia.
Median progression free survival was 9 months (95 % CI); at a median
follow up of 36 months 75% patients remained alive [55].
Dermatofibrosarcoma protuberans
Dermatofibrosarcoma Protuberans (DFSP) is an uncommon, low
grade STS which originates from cutaneous mesenchymal cells. It is
characterized by slow growth with low rates of invasion and most
commonly occurs in the 20 to 50 years age group. The most common
mechanism involved in the pathogenesis of dermatofibrosarcoma is
rearrangement of chromosome 17 and 22, leading to activation of
Platelet Derived Growth Factor (PDGF), which acts as a stimulus for
tumor growth.
The most common treatment modality is complete surgical
resection with microscopically negative margins. For locally
unresectable/metastatic DFSP, tyrosine kinase inhibitor, imatinib
has been approved for treatment. This is based on a phase II trial
with imatinib 400 vs. 800 mg in patients with locally advanced or
metastatic DFSP. This showed Objective response rate of 50% in
imatinib group. There was no significant difference in response rate
and Time To Progression (TTP) between 400 mg vs. 400 mg dosing
[56,57].
Alveolar soft part sarcoma
Alveolar soft part sarcoma is a rare malignancy which accounts
for 0.8% of STS. It usually arises in soft tissue or bone mostly affecting
patients younger than <35 years. Due to the extreme vascular nature
of the tumor, early metastasis, frequently at the time of presentation
is common [58].
In a phase II trial, cediranib, a VEGFR (Vascular Endothelial
Growth Factor Receptor)-1,2, 3inhibitor, showed 35% objective
response rate and disease control rate of 84% at 24 weeks [59].
In another study, Sunitinib, a TKI (Tyrosine Kinase Inhibitor)
with anti VEGF activity showed median progression free survival of
19 months with 86% patients being free of progression at 6 months.
Median overall survival was 56 months. Most common toxicities
were neutropenia, thrombocytopenia, hypothyroidism and arterial
hypertension [60].
Newer approaches with immune check point inhibitors, targeted
drug combinations and tumor vaccines are active in this subtype of
sarcoma [61].
Dendritic cell and histiocytic sarcoma
Hematopoietic tumors originating from CD 34 + myeloid
progenitor cells include Histiocytic Sarcoma (HS), Langerhans Cells
Histiocytosis/Sarcoma (LCH) and Interdigitating Dendritic Cell
Sarcoma (IDCS), whereas stromal or mesenchymal derived tumors
include Follicular Dendritic Cell Sarcoma (FDCS) and fibroblastic
reticular cell tumors.
A retrospective analysis was conducted on patients with FDCS,
IDCS, and HS to evaluate the impact of surgery, radiation and
systemic therapies on overall survival. Results showed that with
surgical management, patients with localized disease had significant
improvement in overall survival than those with metastatic disease
in FDCS (p =0.04) and IDCS (p =0.014) but no significant difference
in HS group (p =0.95). Adjuvant radiotherapy and neo adjuvant
chemotherapy with doxorubicin and ifosfamide regimens did not
show significant improvement in overall survival. In IDCS, a 5 year
overall survival rate of 71 % was noted with surgery alone [62].
For localized FDCS, surgical resection is the treatment of choice.
Analysis of 66 patients with advanced FDCS showed an overall
response rate of 80% in 10 patients who received gemcitabine and a
taxane (2 complete responses); and the median response duration was
13.4 months (range 3 to 83 months). Partial responses were noticed in
3 patients who received ifosfamide and doxorubicin based regimens
and in one of the 2 patients who were treated with an anthracycline
based regimen (CHOP: cyclophosphamide, doxorubicin, vincristine,
prednisone) [63].
Peritoneal sarcomatosis in pediatric malignancy
Peritoneal Sarcomatosis (PSC) is characterized by peritoneal
involvement of multiple sarcomatous tumors. The most common
pediatric PSC are seen in Desmoplastic Small Round Cell Tumors
(DSRCT) and rhabdomyosarcoma. Chemotherapy and palliative
surgery are the common treatment practices, but long-term outcomes
were poor.
Some of the newer treatment modalities such as Cytoreductive
Surgery (CRS) followed by Hyperthermic Intraperitoneal
Chemotherapy (HIPEC) have resulted in prolonging remission in
pediatric population [64].
Results from a prospective database of patients who underwent
CRS/HIPEC showed that median intraabdominal disease free and
overall survival after CRS/ HIPEC were 17.2 (95% CI: 2.4 - 19.7) and
22.6 months (95% CI: 6.1 - 62.6 months) respectively. The recurrence
rate with CRS/ HIPEC Vs CRS only was 17.2 Vs 10.7 months (p
=0.52) [65].
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
Table 8
Table 8
Proposed treatment sequence for advanced or metastatic, high-grade soft tissue sarcoma [66].
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