A Review of Neoadjuvant

Chemoradiation Strategies in the

Treatment of Extremity Soft Tissue
Sarcomas
An ESUN Article by Kelly S. Perlewitz, MD and Christopher W. Ryan, MD

Introduction
Soft tissue sarcomas are a rare, heterogeneous group of tumors
that account for approximately 1% of all adult cancers.1 While they
may be found in nearly any site of the body, the upper and lower
extremities are the most common locations, accounting for about
50% of all cases. High-risk soft tissue sarcomas of the extremity
include those that are large (>5cm) and of intermediate or highgrade. While the mainstay of historical treatment was amputation,
current limb sparing surgery approaches combine wide excision
with radiation therapy, an approach that yields local control rates of
close to 90%.2-5 Despite excellent local control rates and the ability
to save the limb in most patients, approximately 50% of patients
with high-risk soft tissue sarcomas of the extremity will die from
metastatic disease.6 In attempt to improve this outcome, systemic
treatment withchemotherapy is often used to eradicate micrometastatic disease and improve outcome; however, results of
adjuvant chemotherapy trials have been mixed and the optimal
management of these tumors remains controversial.7
One approach to the treatment of high-risk soft tissue sarcomas of
the extremities is the use of combination pre-operative
(neoadjuvant) chemotherapy and radiation. In addition to early
treatment of micro-metastatic disease, pre-operative chemotherapy
may act as a radiation-sensitizing agent to decrease the chance of
local recurrence. This review will examine pre-operative
chemoradiation strategies in the treatment of soft tissue sarcomas.
High-risk soft tissue sarcomas are deep tumors of high pathologic grade and > 5
cm in size. While surgery and radiation are usually effective in eradicating the

tumor from the affected limb, their tendency for early, microscopic spread places
patients at significant risk for eventual development of metastatic disease.

Pre-operative vs. Post-operative

Radiation
The addition of radiation to standard surgical treatment of extremity
soft tissue sarcomas has allowed for limb-salvage surgeries to
become the norm rather than the exception.2-5 Whether radiotherapy
should be administered in the pre- or post-operative setting has
been a topic of debate. Advantages to pre-operative radiotherapy
include delivery of radiation to well-oxygenated tissue that has not
been disturbed. Additionally, lower radiation doses may be used and
the field size does not need to be increased to cover a surgical
incision.
A randomized trial of 190 patients with extremity soft tissue
sarcoma comparing pre-operative (50 Gy in 25 fractions) vs. postoperative radiotherapy (66Gy in 33 fractions) was performed by the
Canadian Sarcoma Group.8 The primary endpoint was the rate of
wound complications. After a median follow-up of 3.3 years, wound
complications were significantly higher in the pre-operative group
(35% vs. 17% respectively, p=0.01). There was no difference in
local recurrence rate, regional failure rate, distant failure rate or
progression-free survival. The pre-operative group did have a
slightly increased overall survival (85% vs. 72%, p=0.05). Wound
complications occurred more frequently in lower extremity (43%)
than in upper extremity (6%) tumors.
Limb-sparing surgical approaches usually require the addition of radiation in order
to reduce the chance of tumor recurrence in the limb. While the effectiveness in
preventing recurrence is the same, side effects may be different depending on
whether radiation is given before or after surgery.

A follow-up analysis of this trial reported on late radiation morbidity

and found that patients treated with post-operative radiotherapy
had a higher rate of grade 2 or greater fibrosis (48.2% vs. 31.5%
respectively, p=0.07).9 Joint stiffness (23.2% vs. 17.8%, NS) and
edema (23.2% vs. 15.1%, NS) were also more frequently observed
in the post-operative radiotherapy arm as opposed to the pre-

operative arm, although these differences were not statistically

significant.
Together, these results suggest that pre-operative radiotherapy is
associated with more acute wound healing complications in the perioperative period, but that the higher radiation dose and larger field
size of post-operative administration may increase long-term limb
complications. Preference for the use pre- vs. post-operative
radiation remains institution-dependent, and may be influenced by
the location of the tumor given the higher incidence of wound
complications in lower extremity tumors.

The Role of Chemotherapy

The two most active chemotherapy agents in the treatment of
metastatic soft tissue sarcoma are doxorubicin and ifosfamide.
Earlier administration of chemotherapy in the course of the disease
can theoretically treat micro-metastatic disease and decrease the
rate of distant disease and improve overall survival. However,
results of studies have been mixed and the use of chemotherapy as
an adjunct to surgery and radiation for high-risk tumors remains
controversial.7,10,11 The optimal schedule and timing for
chemotherapy in this setting remains undefined. Most randomized
trials to date have investigated the role of post-operative
chemotherapy, and relatively few pre-operative trials have been
reported.
Gortzak et al examined neo-adjuvant chemotherapy using
doxorubicin and ifosfamide vs. no pre-operative therapy in a small
randomized study of patients with high-risk soft tissue sarcomas.12
This study demonstrated the feasibility of chemotherapy prior to
surgical resection without adversely affecting surgery or subsequent
radiotherapy. While there was not a statistically different 5-year
disease-free or overall survival, this 134-patient study was
underpowered to draw definitive conclusions regarding these
outcomes.
A multi-institutional, retrospective analysis of patients treated with
neoadjuvant chemotherapy containing
doxorubicin/ifosfamide/mesna vs. those treated with surgery alone

was reported by Grobmyer et al.13 Improved 3-year disease specific

survival was seen for patients with tumors >10 cm treated with
neoadjuvant chemotherapy vs. those treated with surgery alone (HR
0.45, 95% CI: 0.25-0.83), suggesting a possible benefit for very
high-risk tumors.
The effectiveness of chemotherapy in improving survival from high-risk soft tissue
sarcomas remains controversial. Some studies have suggested that chemotherapy
helps, while others have not. Further studies in patients with high-risk tumors and
select sarcoma subtypes are needed.

Neoadjuvant Chemoradiotherapy
Theoretical advantages of neoadjuvant chemotherapy together with
pre-operative radiation include earlier treatment of micro-metastatic
disease and a lower radiation dose requirement. Neoadjuvant
chemoradiotherapy may possibly help to downsize the tumor
allowing for a more-resectable tumor and possibly less morbid
procedure. Additionally, pathologic response determined at the time
of surgical resection provides potential prognostic information. While
the most important role of neoadjuvant chemotherapy is its
potential effect on reducing development of metastatic disease, its
activity as a radiosensitizer may help improve local control rates
when combined with radiation.14 While surgery occurs several
months later when a neoadjuvant approach is employed, there is no
evidence of worse outcome because of what may be perceived as a
delay by patients.15

Table I: Published Reports of Neoadjuvant Chemoradiotherapy

Multi-modality approaches using neoadjuvant chemoradiotherapy

for high-risk soft tissue sarcomas have been pursued by a number
of institutions. Reports of neoadjuvant chemoradiotherapy in this
population have consisted of single-arm studies and retrospective
analyses (Table 1). As with much other clinical research in sarcoma,

the absence of large, randomized trials and Level I evidence limits

interpretation of such data. Early strategies employed regional
chemotherapy with intra-arterial doxorubicin. Eilber et al reported
on consecutive patients treated at UCLA between 1975-1981 with
bone and soft tissue sarcomas (n=100) using intra-arterial
doxorubicin at 30 mg/day over 24-hours for 3 consecutive days
followed by a rapid fractionation radiation plan of 350 cGy/day for
10 treatments (3500 cGy).16 With a median follow-up of 32-months
the local recurrence rate was only 3%. Patients with grade III
tumors between 5-10cm had an overall survival of 76% while
patients with larger tumors (10-15cm) had 65% overall survival. A
subsequent trial reducing the radiation dose (1750 cGy), resulted in
an increased local recurrence rate of 20% with only 4% of subjects
achieving a complete pathologic response; subsequent trials from
this group have used the 2800 cGy dose.15
Multiple other reports of pre-operative intra-arterial doxorubicin with
high-dose per fraction, short course radiation were subsequently
reported.15,17-22 These studies employed similar radiation schemes and
reported very low local recurrence and promising disease-free
survival rates. The cumbersome and potential toxic effects of intraarterial chemotherapy were eventually questioned.22 A randomized
trial from the UCLA group demonstrated that there was no
difference in local control or complication rates between intraarterial vs. intravenous doxorubicin combined with radiation
(n=112).23 This trial showed a 6% complete pathologic response,
14% local recurrence rate, and 70% overall survival. Subsequent
studies transitioned to the use of intravenous chemotherapy, with
similar outcomes reported as with intra-arterial therapy.
More recent studies of neoadjuvant chemoradiotherapy have
employed multi-agent chemotherapy.15,24-30 In the metastatic setting,
combination chemotherapy has been associated with greater
response rates than single-agent doxorubicin, though without clear
survival advantage.31,32 In the adjunctive, minimal disease setting, it
is hoped that potential additional activity of combination treatment
may translate into increased clinical benefit. Most recent
neoadjuvant regimens have employed anthracycline and ifosfamide
combinations.15,24-30

DeLaney et al reported a 48 patient study from the Massachusetts

General Hospital using neoadjuvant chemotherapy and
"interdigitated" radiotherapy for 8 cm or larger, high-grade
extremity soft tissue sarcomas.26 Pre-operative treatment consisted
of 3 pre-operative cycles of the MAID regimen (mesna, doxorubicin,
ifosfamide, and dacarbazine) with 2 radiotherapy courses
sandwiched between cycles to a total of 44Gy. Three additional
cycles of MAID chemotherapy were given post-operatively. Toxicities
of this treatment regimen included febrile neutropenia (25%), moist
desquamation of skin (29%), grade 3 nausea (17%), grade 3
vomiting (10%), wound healing complications (29%), and
myelodysplasia as a late complication in 1 patient. Five-year
outcomes compared with historical controls included improved
freedom for distant metastasis 75% vs. 44% (p=0.0016), diseasefree survival 70% vs. 42% (p=0.0002), and overall survival 87%vs.
58% (p=0.0003), respectively. While such retrospective
comparisons must be interpreted cautiously, these data were
encouraging and prompted the initiation of a confirmatory Radiation
Therapy Oncology Group (RTOG) multi-institutional trial.33 The 66
patient RTOG 9514 trial reported significant toxicity including 3
treatment-related deaths and an 83% incidence of grade 4 toxicity.
The 5-year disease-free survival of 56% and overall survival of 71%
were less robust than the single institution experience, suggesting
that while a complicated neoadjuvant chemoradiotherapy regimen
could be delivered in a multi-institutional setting, its general
applicability outside of a dedicated center remained questionable.
Potential advantages of neoadjuvant chemoradiotherapy
Early treatment of micro-metastases
Lower radiation doses
Shrinking the tumor for surgery
Prognostic information gained from the surgical specimen.
Potential disadvantages of neoadjuvant chemoradiotherapy
Increased wound complications
Delay of surgery

Ryan et al investigated the use of an intensive chemotherapy

regimen with ifosfamide and epirubicin in combination with preoperative hypofractionated radiation in patients with high-risk soft
tissue sarcomas of the extremity or body wall.28 Three pre- and 3

post-operative cycles of epirubicin and ifosfamide were administered

at relatively high doses similar to those used in a randomized
adjuvant trial.10 During the second pre-operative cycle, epirubicin
was omitted and radiotherapy to 28Gy administered in 8 fractions,
similar to the regimens reported by Eilber et al.15 The primary
endpoint was rate of =95% pathologic necrosis at time of surgical
resection which was reported at 40% (95% CI, 21-59%). Two-year
disease-free and overall survival were 62% (95% CI, 37-86%) and
84% (95% CI, 66-100%), respectively. Toxicity was significant with
84% of patients experiencing grade 4 toxicities. Grade 3/4 anemia
(64%), ifosfamide-induced encephalopathy (24%), and neutropenic
fever (40%) were the most notable toxicities. A 20% post-operative
wound complication rate was also seen. This study demonstrated
that an intensive neoadjuvant chemoradiotherapy strategy could
yield a significant pathological necrosis rate but with substantial
toxicity.
The trials of neoadjuvant chemoradiotherapy to date have enrolled a
heterogenous population of soft tissue sarcoma subtypes due to the
inability of single institutions to effectively conduct histology-specific
studies. As certain soft tissue sarcoma subtypes are generally
considered to be more chemotherapy-sensitive (e.g. synovial
sarcoma, myxoid round cell liposarcoma), outcomes of neoadjuvant
approaches in such histologies are of interest and some
retrospective attempts have been made to discern benefit. Data
from 245 patients with high-risk liposarcoma of the extremities
treated at UCLA and Memorial Sloan Kettering were analyzed based
on whether they had received neoadjuvant or adjuvant ifosfamidebased, doxorubicin-based, or no chemotherapy.34 On multivariate
analysis, treatment with ifosfamide was independently-associated
with improved disease-specific survival (HR = 0.3 compared with no
chemotherapy, P = 0.01). A similar analysis of 101 patients with
high-risk synovial sarcomas also suggested a disease-specific
survival benefit with ifosfamide over no chemotherapy (HR = 0.3, P
= 0.007).35However, a retrospective report of 100 patients with
synovial sarcoma treated with pre-operative ifosfamide and
radiation followed by post-operative ifosfamide, doxorubicin and
cisplatin reported an estimated 5-year disease-free survival rate of
50%, which is not suggestive of improved outcome compared with

the overall soft tissue sarcoma population.30 While there are no

definitive data supporting the neoadjuvant chemoradiotherapy
approach in any particular soft tissue sarcoma subtype, its use
especially in chemotherapy-sensitive subtypes is a strategy
employed by some centers.
Combined preoperative chemotherapy and radiation strategies should be primarily
considered for patients with high-risk sarcomas (> 5 cm, high-grade, deep tumors).
The relative effectiveness in individual sarcoma subtypes has not been defined, but
special consideration may be given to sarcomas thought to be more responsive to
chemotherapy, such as synovial sarcoma or myxoid round cell liposarcoma.

Histopathologic Response to Neoadjuvant

Therapy

Figure 1. Example of = 95% pathologic necrosis response...

One potential benefit to the use of pre-operative therapy is the

information gained from examination of the surgical specimen after
resection (Figure 1). While pathologic necrosis to pre-operative
chemotherapy has been established as a prognostic factor in
osteosarcoma and Ewings sarcoma,36,37 relatively little has been
published regarding its value in soft tissue sarcomas. The UCLA
group reported on treatment-induced pathologic necrosis as a
predictor of local recurrence and survival in a retrospective analysis
of 496 soft tissue sarcoma patients treated with neoadjuvant
therapy at their institution.38 Ten-year local recurrence rates were
lower in patients with =95% necrosis (11% vs. 23%, respectively)
and 10-year overall survival was likewise higher in patients with
=95% necrosis (71% vs. 55%, respectively).
MacDermed et al demonstrated a positive correlation between
treatment-induced pathologic necrosis and freedom from distant
metastasis in a retrospective study of neoadjuvant rapid

fractionation radiation with ifosfamide-based chemotherapy.29Fifty

percent of tumors demonstrated =90% treatment-induced necrosis.
Freedom from distant metastasis was superior in the patients who
had =90% treatment-induced necrosis (84.6% vs. 19.9%, p=0.02).
However, for the overall population the 5-year overall survival rate
of 42.3% was less than reported in the other series.
The trial by Ryan et al was unique in its use of histopathologic
response as the studys primary endpoint.28 Validation of pathologic
necrosis as a surrogate endpoint should be considered in future
prospective trials of pre-operative therapy for soft tissue sarcomas.
Early detection of response to neoadjuvant therapy with imaging
modalities such as PET or DCE-MRI may likewise provide important
predictive information and are actively being studied in this
setting.39-41

Future Directions
Collectively, phase II trials have shown high rates of local control
and histologic response with neoadjuvant chemoradiotherapy for
extremity soft tissue sarcomas. While overall survival rates are
favorable, benefit cannot be proven in the absence of randomized
trials and a significant proportion of high-risk patients still succumb
to the disease. New approaches are needed to advance treatment
options and to provide alternatives to current neoadjuvant
chemotherapy regimens with their associated significant toxicity.
Refinement of the radiation component of pre-operative therapy is
one current area of investigation. RTOG 0630 is a phase II study of
image-guided pre-operative radiotherapy for primary extremity soft
tissue sarcomas aimed at reducing late radiation morbidity.42 This
study consists of 2 cohorts. Subjects in cohort A will receive
neoadjuvant and/or adjuvant chemotherapy plus 50Gy of radiation
in 25 daily fractions, or concurrent or interdigitated chemotherapy
plus 44Gy of radiation in 22 daily fractions. Subjects in cohort B are
those not receiving chemotherapy who will receive 50Gy of radiation
in 25 daily fractions. All subjects will then receive surgery followed
by a post-operative radiotherapy boost in those subjects with
positive margins. Cohort A closed in January 2010 and results are
pending.

A promising adjunct to neoadjuvant therapy is regional

hyperthermia, a process in which tumor tissue is heated to improve
the effects of chemotherapy or radiation. In a recently published
phase III trial, 341 patients with large, high-grade sarcomas (both
extremity and non-extremity) were randomized to neoadjuvant
chemotherapy (etoposide, ifosfamide, and doxorubicin) with or
without concurrent hyperthermia.43 Local progression-free survival
(LPFS) was improved in the hyperthermia group (HR 058, 95% CI
041083; p=0003), with 2-year LPFS of 76% in the
chemotherapy plus regional hyperthermia group vs. 61% in the
chemotherapy-alone group. While hyperthermia in conjunction with
pre-operative chemoradiotherapy has not yet been reported, an
ongoing phase II study is investigating such an approach using
ifosfamide, radiation, and hyperthermia and employing magnetic
resonance imaging for non-invasive hyperthermia monitoring.44
Another unique neoadjuvant modality is isolated limb perfusion, a
technique in which the blood supply to the limb is isolated from the
rest of the body through extracorporeal circulation, allowing the
infusion of high doses of biochemotherapy into the affected limb.
Tumor necrosis factor-alpha (TNF-, available only in Europe) is
infused together with chemotherapy agents such as melphalan,
often under mild hyperthermic conditions.45,46 While this treatment is
not used in combination with radiation and full discussion is out of
the scope of this review, its high response rates and potential utility
in large, unresectable sarcomas is worthy of mention.
Integration of novel systemic agents with neoadjuvant
chemoradiotherapy is another strategy that is being explored.
Okuno et al reported on the use of aerosolized GM-CSF in attempt
to decrease the development of pulmonary metastatic disease when
given with a pre-operative regimen of ifosfamide, mitomycin,
doxorubicin, cispalatin and radiation.47 This was considered a
negative study by the authors as the 2-year pulmonary-metastasis
free rate of 75% (95%CI 62-91%) was no better than their
historical experience with chemoradiotherapy alone.
Anti-angiogenic agents have held promise in the treatment of
sarcoma.48,49 The RTOG investigated the addition of thalidomide to
pre-operative MAID chemotherapy with interdigitated radiation

followed post-operatively by 12-months of adjuvant

thalidomide.50 Unfortunately 40% of subjects had grade 3/4 vascular
adverse events leading to early closure of the study. Our group at
Oregon Health & Science University is investigating the addition of
the vascular endothelial growth factor (VEGF) receptor tyrosine
kinase inhibitor, sorafenib, to our previously reported regimen of
pre-operative epirubicin/ifosfamide and hypofractionated
radiation.28 We are also studying whether DCE-MRI can detect early
changes in tumor perfusion during treatment with anti-angiogenic
therapy.41
As the field of oncology continues to elucidate the molecular
pathways that regulate tumor growth and progression, it will
become increasingly important to match individual tumors with
appropriate targeted therapeutic agents. The pre-operative
treatment period provides an invaluable setting in which to test
agents based on analysis of biopsy specimens. Comparison of the
post-therapy surgical specimen with baseline biopsy material may
reveal important clues as to mechanisms of drug resistance, and
such approaches should be incorporated in future studies of
neoadjuvant therapy.

Conclusions
Multi-disciplinary treatment of soft tissue sarcomas is paramount for
optimal outcome. Wide surgical excision with the addition of
radiotherapy remains the mainstay of treatment of locally advanced
soft tissue sarcomas. Neoadjuvant chemoradiotherapy has thus far
been studied in relatively small, non-randomized trials. Therefore
the impact of these approaches on patient outcomes remains
speculative. While centers with dedicated treatment teams have
reported good outcomes with neoadjuvant chemoradiotherapy, the
overall benefit and general applicability of such regimens remains
unknown in the absence of multi-center, randomized trials. Further
progress will be dependent upon the discovery of new and active
treatments for soft tissue sarcomas that can be tested in the highrisk setting.
Last revision and medical review: 4/2011

by Kelly S. Perlewitz, MD
and Christopher W. Ryan, MD
Oregon Health and Science University
Knight Cancer Institute
Portland, OR
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