Factors Influencing Prognosis After Initial Inadequate Excision (IIE) for Soft Tissue Sarcoma.

Abstract

Purpose. The influence of initial inadequate excision (IIE) of soft tissue sarcoma (STS) on local control and overall survival is not well established. It is generally believed that an IIE may have a negative impact on both, despite subsequent treatment by radical surgery and radiotherapy. However, data on local recurrence-free survival/overall survival are conflicting and there are no data on the effect of IIE on overall survival.Patients and methods. A retrospective analysis was made of 86 patients with soft tissue sarcoma of the extremities and trunk after an IIE had been performed due to inappropriate work-up. The minimal follow-up was 7 years. Specimens of the subsequent radical resection were evaluated for residual tumor, grade of tumor and complications of IIE. Endpoints were recurrence-free survival and overall survival.Results. Specimens of the subsequent radical resection showed residual tumor in 66 patients (77%). The most common complication after IIE was hematoma. In both univariate and multivariate analyses, grade II/III tumors and complications after IIE are significant negative prognostic factors for local recurrence-free survival (P = 0.008 and P = 0.002, respectively, in the Cox model). For this survival, three prognostic groups could be formed based on grade, or presence or absence of complications. Adjuvant radiotherapy did not change the rate of local recurrence-free survival. For overall survival, only tumor grade is a significant factor (log-rank test).Conclusion. This retrospective study shows that complications associated with an IIE have a significant negative effect on local control, but not on overall survival, because IIE is often the result of inappropriate work-up before surgery. For better diagnosis and therapy STS should be treated in specialized centers.

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Sarcoma, September/December 2003, VOL. 7, NO. 3/4, 159–165
ORIGINAL ARTICLE
Factors influencing prognosis after initial inadequate excision (IIE)
for soft tissue sarcoma
ALBERT N. VAN GEEL1, ALEXANDER M.M. EGGERMONT1,
PATRICK E.J. HANSSENS2& PAUL I.M. SCHMITZ3
Departments of1Surgical Oncology,2Radiotherapy and3Trials and Statistics, University Hospital Rotterdam/Daniel
den Hoed Cancer Center, Rotterdam, The Netherlands
Abstract
Purpose.
is not well established. It is generally believed that an IIE may have a negative impact on both, despite subsequent treatment
by radical surgery and radiotherapy. However, data on local recurrence-free survival/overall survival are conflicting and there
are no data on the effect of IIE on overall survival.
Patients and methods.
A retrospective analysis was made of 86 patients with soft tissue sarcoma of the extremities and trunk
after an IIE had been performed due to inappropriate work-up. The minimal follow-up was 7 years. Specimens of the
subsequent radical resection were evaluated for residual tumor, grade of tumor and complications of IIE. Endpoints were
recurrence-free survival and overall survival.
Results.Specimens of the subsequent radical resection showed residual tumor in 66 patients (77%). The most common
complication after IIE was hematoma. In both univariate and multivariate analyses, grade II/III tumors and complications
after IIE are significant negative prognostic factors for local recurrence-free survival (P¼0.008 and P¼0.002, respectively,
in the Cox model). For this survival, three prognostic groups could be formed based on grade, or presence or absence of
complications. Adjuvant radiotherapy did not change the rate of local recurrence-free survival. For overall survival, only
tumor grade is a significant factor (log-rank test).
Conclusion.
This retrospective study shows that complications associated with an IIE have a significant negative effect on
local control, but not on overall survival, because IIE is often the result of inappropriate work-up before surgery. For better
diagnosis and therapy STS should be treated in specialized centers.
The influence of initial inadequate excision (IIE) of soft tissue sarcoma (STS) on local control and overall survival
Key words: soft tissue sarcoma, surgery, prognostic factors, local recurrence, survival
Introduction
Soft tissue sarcoma (STS) is a group of anatomical
and histological diverse malignancies of mesen-
chymal tissue. STS is a rare condition: in the USA
there are about 7000 new cases and 4300 deaths
each year.1
Local control of STS mainly depends on the
extent of surgical treatment. The most effective local
control is achieved by resection of the tumor with
clear margins; however, the definition of radical
resection is still debated. The definition varies from
wide resection to compartment resection and myect-
omy, with less radical resections being defined as
marginal or intralesional ones. The local recurrence
rate of these latter resections ranges from 60 to 95%,
whereas the local recurrence rate of radical resection
ranges from 5 to 30%.2–4When a radical resection
cannot be achieved, radiotherapy can improve the
local control rate, but will rarely match the better rate
of radical resections. Improved local control rate is
not reflected in a better disease-specific survival.5
Brachytherapy is reported to achieve better local
control than conventional radiotherapy, especially
for high-grade sarcomas.6
Other factors influencing the local control rate are
tumor size, depth, retroperitoneal and visceral
localizations, and histological grade.7
In addition, factors such as age or specific
histological types have occasionally been reported.8,9
In practice, a substantial number of patients
undergo a marginal resection because the tumor
Correspondence to: A.N. van Geel, MD, PhD, Department of Surgical Oncology, Erasmus Medical Center—Daniel den Hoed Cancer
Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands. Tel.: þ31-10-4391793; Fax: þ31-10-4391011; E-mail:
geel@chih.azr.nl
1357-714X print/1369–1643 online ? 2003 Taylor & Francis Ltd
DOI: 10.1080/13577140310001650321

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has not been recognized as a STS. After the
pathological diagnosis of STS is established, a
subsequent treatment must be performed, preferably
by a radical resection whether or not in combination
with radiotherapy. There are few data on the effect of
these unplanned initial inadequate resections (IIE)
with no clear margins on local recurrence rate,9–11
and no data at all on survival. This issue also has
been studied, with conflicting results, only in patients
with an incisional biopsy, a problem that may be
closely related to an IIE.3,12
Patients and methods
All records of 263 patients with STS referred for
surgery to the University Hospital Rotterdam/Daniel
den Hoed Cancer Center between 1986 and 1993
were reviewed. Excluded from this study were those
patients with a local recurrence and/or distant
metastases at time of referral. Retrospectively, those
patients were identified who had a previous irradical
resection for diagnostic reasons, which could not be
classified as an incisional biopsy. Only patients with
STS in the limbs, girdles and trunk were entered in
this study because, in these patients, a radical treat-
ment (radical resection, marginal resection with
radiotherapy or amputation) is always possible. Small
superficial tumors (?5cm) were also excluded.
Pathological examination was carried out in our
hospital, on all resected specimens of all patients,
also when the initial surgery was performed in
another hospital. Excluded from this study were
those pathological subtypes of STS that need a
non-surgical approach as the first-line treatment
(e.g., small round-cell sarcomas such as Ewing
sarcoma), or subtypes with a specific biological
behavior such as borderline tumors (e.g., aggressive
fibromatosis and desmoids), because they do not
give distant metastases.
For statistical reasons it was decided to include
only patients treated before 1993, thus assuring a
follow-up period of at least 7 years in all patients.
In our records we found 86 patients (32.7% of all
patients referred for treatment) fulfilling the above-
mentioned criteria. The following data were collec-
ted: age at the time of diagnosis, tumor site, date and
type of initial surgery (excision or debulking),
complications of this procedure (hematoma, infec-
tion), type of incision, residual tumor seen on CT or
MRI after initial surgery, date and type of subse-
quent definitive surgery, whether definitive surgery
was preceded by an isolated limb perfusion, and
whether definitive surgery was followed by adjuvant
radiotherapy and/oradjuvant
Histopathological work-up included: whether a
macro- or microscopical residual tumor was seen at
pathological examination, total diameter of the
tumor, including the size of the IIE, and pathological
type andgrade oftumor.
chemotherapy.
Furthermore,the
complexity of the definitive surgical procedure
was evaluated compared with the one surgical
procedure that would have been performed after an
initial appropriate preoperative work-up. Finally,
data on morbidity, local control and survival were
noted.
Statistical analysis
The
univariate analysis with respect to three endpoints:
time to death, time to local recurrence and time to
distant metastases. Local recurrence-free survival
was calculated for those patients alive at 2, 5 and
10 years. Log-rank tests and Kaplan-Meier survival
analyses were used for all factors and endpoint
combinations for all 86 studied patients. In multi-
variate analysis, only local control was studied using
the Cox proportional hazards model. Based on
the results of the multivariate analysis we formed
three prognostic groups (good, moderate and poor
prognosis).
potentialprognostic factorsunderwent
Results
In this series of 86 patients, there were 47 males and
39 females (age range 17–77 years). The tumor was
located in the lower limb in 39 cases (45%), the
upper limb in 17 (20%), the trunk in 19 (22%) and
in the girdles in 11 (13%). There were 21 superficial
tumors larger than 5cm and 65 deep, subfacial
tumors.
In 51 patients (60%), the operation was consid-
ered to be an excisional biopsy. In the remaining 35
patients (40%), only a gross debulking of the tumor
was performed.
At presentation in our hospital, a hematoma
was seen in 20 (23%) of the 86 patients. In three
patients, a wound infection at presentation needed
immediate drainage, and another three patients were
treated by antibiotics. Transverse scars were seen in
15 patients.
Within 3–4 weeks after referral, a CT scan or MRI
was performed for local staging. In 40 patients
(46%), no residual tumor could be found. In the
remaining 46 patients (54%), there were changes
in the surgical field that could not be explained by
the previous surgery alone, with a strong suspicion of
macroscopic tumor remnant being present. In the
resected specimens, residual tumor was found in 66
patients (77%).
On pathological examination, liposarcoma was the
most common subtype and was found in 17 patients
(20%), all other types represented less than 10% of
the STS.
The tumor was graded according to Trojani as
follows: grade I in 28 patients (33%), grade II in
44 (51%) and grade III in 14 (16%).
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The diameter of the tumor was: T1 (?5cm) in 41
patients and T2 (>5cm) in 45 patients.
In the absence of distant metastases, all patients
underwent a radical treatment for their primary
lesion: whenever feasible, a radical resection was
performed (n¼45) and in other cases a less radical
resection with adjuvant radiotherapy (n¼33). In
our institute, a radical resection is defined as a
resection of the tumor with a free margin of at least
1cm at pathological examination, or less than 1cm
when, at that margin, fascia, periostium or perichon-
drium is present. Four patients did not receive
further treatment after IIE and another four patients
received only radiotherapy.
Radiotherapy was delivered to the target area
(compartment or field round the tumor bed with a
margin of 5–7cm length and 2cm transverse) at a
dosage of 50Gy in 25 fractions, with a boost on the
tumor bed of 10Gy in five fractions. The total
dosage was increased to 70Gy in cases of limited
resection margins.
In five cases, an isolated limb perfusion was
the initial treatment in order to prevent amputation
ormajor functionalmorbidity.
were treated in the context of the EORTC protocol
10863 with neoadjuvant chemotherapy (doxorubicin
Fivepatients
50mg/m2and ifosfamide 5mg/m2i.v.q. 3 weeks,
three courses) and were excluded from multivariate
analysis for local recurrence rate because they were
recognized as high-risk patients.
In 50% of patients, the definitive surgery was
considered to be more complex and resulted in
more morbidity than could be expected had the
tumor been diagnosed and treated in the proper way
at first presentation. In 71 patients (82%), the
postoperative course was uneventful.
All patients were followed for 7 years or longer.
Of the total group, 25 patients (29%) developed a
local recurrence and 28 patients (33%) distant
metastases; 14 patients (16%) had both local and
distant recurrent disease.
At the close of the study, 52 patients (60%)
were still alive without any evidence of STS and
four patients (5%) were alive with evidence of
recurrent tumor. A total of 30 patients (35%) had
died, five of whom died from intercurrent diseases.
Table 1 gives data on overall survival, local
recurrence-free and distant recurrence-free survival
at 2, 5 and 10 years follow-up.
Table 2 lists the prognostic parameters investi-
gated and Table 3 gives the results of the univariate
analyses.
Table 2. Study parameters of 86 patients with an unplanned excision of soft tissue sarcoma
Potential prognostic factors
1. Age at the date of the first operation
2. Gender
3. Localization of the primary: lower limb, upper limb, trunk (abdominal wall, back, and buttock) and girdles (axilla
and groin)
4. Complication after the first operation: hematoma
5. Definitive surgery: radical resection þ/? isolation perfusion or amputation, less radical resection þ/? isolation perfusion
and radiotherapy, no therapy and radiotherapy alone
6. The definitive surgical procedure was more complex than could be expected had proper diagnosis and treatment
taken place initially. Also, that adjuvant radiotherapy could be avoided in case of residual macroscopical tumor or
microscopical high-grade tumor)
6. Tumor diameter before any treatment
7. Histopathological diagnosis (liposarcoma, all other types of sarcoma)
8. Grade according to Trojani
9. Macroscopical residual tumor seen at CT scan or MRI after initial surgery
10. Microscopical residual tumor found only at histopathological examination
11. Data of follow-up (date of local recurrence and/or distant metastases, last date of follow-up and survival status)
Follow-up Data
1. Survival status and date of death or last date of follow-up
2. Local recurrence status and date of local recurrence (if occurred)
3. Distant metastases status and date of distant metastases (if occurred)
Table 1. Survival data of 86 patients with an initial irradical excision for soft tissue sarcoma
Overall
survival (%)
Local recurrence-free
survival (%)
Distant recurrence-free
survival (%)
2 years
5 years
10 years
86
75
55
86
74
65
85
74
56
Initial inadequate excision
161

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The Cox proportional hazards model was used to
determine local recurrence-free survival. Only comp-
lication (P¼0.002) and tumor grade (P¼0.008)
appeared tobeindependent prognosticfactorsforthis
endpoint. Based on these two factors, three prognos-
tic groups were created. These groups (defined as
good, moderate and poor) are described in Table 4
and the local recurrence-free survival is shown in
Figure 1.
Table 5 presents data on the local recurrence-free
survival for the three prognostic groups, with or
without radiotherapy.
Fig. 1. Local recurrence-free survival curves of 81 patients with initial irradical excision for soft tissue sarcoma: group I, good prognosis
(n¼23); group II, moderate prognosis (n¼43); group III, poor prognosis (n¼15).
Table 3. Data (P values) on the potential prognostic factors of initial irradical excision of soft tissue sarcoma in
86 patients (significant p<0.05)
Overall
survival
Local recurrence-free
survival
Distant recurrence-free
survival
Age at diagnosis
Gender
Time to symptoms
Localization
Complication
Definitive treatment
Complexity
Residual tumor
Macroscopic
Microscopic
Diameter
Pathology
Grade
0.08
0.40
0.46
0.12
0.16
0.54
0.16
0.16
0.27
0.99
0.39
0.002
0.006
0.002
0.43
0.11
0.73
0.87
0.048
0.07
0.048
0.18
0.31
0.18
0.43
0.01
0.02
0.17
0.52
0.46
0.004
0.12
0.32
0.25
0.17
0.0003
Table 4. Prognostic subgroups of patients with an initial irradical excision of soft tissue sarcoma (n¼81)
Local recurrence-free survival (%)
Group2 years 5 years 10 years
I (n¼23)
II (n¼43)
III (n¼15)
Good prognosis
Moderate prognosis
Poor prognosis
100
93
67
100
79
37
86
86
37
Group I, grade I and no complication; group II, grade II/III or complication; and group III, grade II/III and
complication.
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A.N. van Geel et al.

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Discussion
Resection of STS with inadequate margins is
considered the most negative prognostic factor in
local recurrence-free survival. As early as 1986,
Suit and Tepper concluded that local recurrence
rates vary according to the initial surgical procedure,
and that improved local control correlates with
better survival.13However, data from many large
studies do not support this conclusion and do not
identify local recurrence as an independent unfavor-
able prognostic factor for survival. In all studies,
tumor grade was the most important and dominant
prognostic factor.14,15
Improvement of preoperative imaging by CT
and MRI and improvement of treatment modalities
(e.g., surgery alone or in combination with radio-
therapyand chemotherapy
isolated limb perfusion) have increased the local
control rate to about 85%.16,17
All patients who have undergone an IIE for
STS are candidates for a second operation in order
to achieve adequate surgical margins. A poorly
performed open biopsy or IIE can change the
definitive surgical treatment in at least 30%.18,19
In the recent literature, we found no data to show
that patients with a radical resection as first
treatment will have a better local recurrence-free
survival than those with a radical resection after IIE
(so-called ‘whoops operation’). Nor could we find
factors in the latter group with an adverse effect
on overall survival.
In some series, the systematic use of an incisional
biopsy is reported to be the cause of higher local
recurrence rates.20However, Collin et al. could
not confirm this statement.12Of note is a recent
study from the Memorial Sloan-Kettering Cancer
Center, which reports better overall survival in
patients with re-resection after previous resection
elsewhere, compared with one definitive resection
in the Cancer Center as primary treatment; this
is especiallysignificant
including regional
for high-gradeSTS.21
The authors then concluded that, where possible,
re-resection should be liberally applied in patients
with primary extremity STS.
For the reasons mentioned above, we studied a
group of patients who had undergone an IIE
elsewhere and who were referred to our center for
definitive treatment.
After 5 years, the overall survival was 75%, the
local recurrence-free survival was 74% and the
distant recurrence-free survival was 74%, these
percentages correspond with data in literature.
Two retrospective studies, similar to ours, also
reported the problem of unplanned excision. In
1996, Goodlad et al. studied 95 patients but did
not report morbidity and follow-up data,10and
Noria et al. investigated 65 patients but included
only extremity sarcomas without evidence of macro-
scopical tumor before second surgery.11We found
residual disease in 66 patients (77%), which is
higher than reported in the latter two series,
i.e., 59 and 35%, respectively. In 20 of the 66
patients in our series and in 25 of the 56 patients
in the Goodlad et al. series, the residual disease
was found only at pathological examination. In
another study by Giuliano and Eilber, the number
of patients with residual bulky disease was the same
as those with residual disease found only at
pathology.22
Because these earlier studies give no information
on the postoperative course and complications after
IIE no comparison can be made with our results,
nor was any information given about the influence
of the first operation on the extent of the definitive
resection and or the number of patients who
subsequently received adjuvant radiotherapy.
When comparing the definitive surgical procedure
with the one procedure that might have been per-
formed after an appropriate preoperative work-up
we realize that ‘more complex’ is a subjective
criterion. Therefore, we give an example to explain
what is intended by ‘more complex surgery’: for
instance, a transverse scar in the extremity can lead
Table 5. Local recurrence-free survival for three prognostic subgroups with or without radiotherapy (n¼81)
Local recurrence-free survival (%)
2 years5 years 10 years
Group without radiotherapy
I (n¼18)
II (n¼21)
III (n¼6)
Group with radiotherapy
I (n¼5)
II (n¼22)
III (n¼9)
Good prognosis
Moderate prognosis
Poor prognosis
100
100
66
100
94
50
80
94
50
Good prognosis
Moderate prognosis
Poor prognosis
100
86
66
100
65
26
100
47
–
Group I, grade I and no complication; group II, grade II/III or complication; and group III, grade II/III and
complication.
Initial inadequate excision
163