Long-term results after resection for soft tissue sarcoma pulmonary metastases.

Abstract

Isolated pulmonary metastases from soft tissue sarcomas (STS) occur in approximately 20% of the cases. Chemotherapy and surgical resection are the current standard treatment options for these patients. Our goal was to identify any prognostic factors for these patients as well as to estimate their long-term survival rate. We examined a series of twenty-two consecutive patients with pulmonary metastases from STS, treated in our institution from 1996 to 2006. Univariate (log-rank and Cox-regression) analysis was performed to identify any significant prognostic factor. Five-year survival rates were estimated by using Kaplan-Meier methods. Four patients (18.2%) were alive without any disease, twelve patients (54.5%) died of disease and we lost all track of six patients (27.3%). Follow-up period ranged from 7 to 75 months. Median follow-up: 14 months, median survival: 19 months. Disease-free interval (DFI) (P=0.005), number of lung nodules (P=0.04) and histology type (P=0.01) were significant prognostic factors at univariate analysis. The overall five-year survival rate was 23.1%. DFI, number of lung nodules at surgery and metastatic histology are significant prognostic factors for patients with resected pulmonary metastases from STS.

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DOI: 10.1510/icvts.2009.204818
2009;
2009;9:223-226; originally published online May 18,
Interact CardioVasc Thorac Surg
Guillén-Grima, Mikel San-Julián, Javier Pardo Mindán and Wenceslao Torre Buxalleu
Carlos E. García Franco, Salvador Martín Algarra, Akiko Tamura Ezcurra, Francisco

Long-term results after resection for soft tissue sarcoma pulmonary metastases
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Long-term results after resection for soft tissue sarcoma
pulmonary metastases
Carlos E. Garcı ´a Franco *, Salvador Martı ´n Algarra , Akiko Tamura Ezcurra , Francisco Guille ´n-Grima ,
Mikel San-Julia ´n , Javier Pardo Minda ´n , Wenceslao Torre Buxalleu
a,
bac
dea
Department of General Thoracic Surgery, Clinica Universidad Navarra (CUN), Avenida Pio XII 36, Pamplona 31008, Spain
Department of Medical Oncology, Clinica Universidad Navarra, Pamplona, Spain
Department of Preventive Medicine, Clinica Universidad Navarra, Pamplona, Spain
Department of Orthopedic Surgery, Clinica Universidad Navarra, Pamplona, Spain
Department of Pathology, Clinica Universidad Navarra, Pamplona, Spain
a
b
c
d
e
Received 9 February 2009; received in revised form 1 April 2009; accepted 8 April 2009
Abstract
Isolated pulmonary metastases from soft tissue sarcomas (STS) occur in approximately 20% of the cases. Chemotherapy and surgical
resection are the current standard treatment options for these patients. Our goal was to identify any prognostic factors for these patients
as well as to estimate their long-term survival rate. We examined a series of twenty-two consecutive patients with pulmonary metastases
from STS, treated in our institution from 1996 to 2006. Univariate (log-rank and Cox-regression) analysis was performed to identify any
significant prognostic factor. Five-year survival rates were estimated by using Kaplan–Meier methods. Four patients (18.2%) were alive
without any disease, twelve patients (54.5%) died of disease and we lost all track of six patients (27.3%). Follow-up period ranged from 7
to 75 months. Median follow-up: 14 months, median survival: 19 months. Disease-free interval (DFI) (Ps0.005), number of lung nodules
(Ps0.04) and histology type (Ps0.01) were significant prognostic factors at univariate analysis. The overall five-year survival rate was
23.1%. DFI, number of lung nodules at surgery and metastatic histology are significant prognostic factors for patients with resected
pulmonary metastases from STS.
? 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
Keywords: Soft-tissue sarcoma; Lung metastases; Resection; Re-do
1. Introduction
Soft tissue sarcomas (STS) are rare tumors of mesenchy-
mal origin with a high mortality ratew1x. Sarcoma may arise
everywhere, but the extremity is the most common primary
site. Isolated pulmonary metastases from STS occur in 20–
50% of these patients and, once the metastatic disease
develops, the prognosis is typically poor w2x, although
prolonged survival is possible for a subset of these patients.
Three-year actuarial survival rates of 40–50% have been
reported for patients whose metastatic disease was com-
pletely resected w3–5x. Most authors consider that pulmo-
nary resection, when feasible, remains the established
treatment approach in patients with metastatic STS to the
lungs. Few data regarding the impact of chemotherapy in
patients undergoing pulmonary resection for STS w2, 6x are
available, but most patients with pulmonary metastases
are treated with chemotherapy at some point in their
clinical course.
In this study we reviewed a cohort of consecutive patients
who underwent resection for STS pulmonary metastases at
our institution. Our main objective was to identify possible
prognostic factors and examine their impact in the overall
*Corresponding author. Tel.: q34948296433; fax: q34948296500.
E-mail address: cegarciaf@unav.es (C.E. Garcı ´a Franco).
survival. Our goal was also to estimate three- and five-year
actuarial survival rates in this group of patients.
2. Patients and methods
After obtaining Institutional Review Board approval, a
comprehensive search on our database was conducted to
identify patients with resected STS lung metastases. From
December 1996 to December 2006, a total of twenty-two
patients underwent STS pulmonary metastases resection at
our institution. At the time of surgery all of these patients
met the following criteria: 1) had their primary STS under
control with multimodality treatment, 2) were considered
preoperatively to have resectable lung metastases, 3) were
deemed eligible for going through lung resection and 4)
were free of metastases in other organs. Most patients had
received an Ifosfamide-Adriamicine based chemotherapy
regimen, either pre or postoperatively: Ifosfamide 6–9
gym qAdriamicine 90 mgym per cycle. The median num-
ber of cycles of preoperative chemotherapy was four (dura-
tion approximately three months). Chemotherapy after
initial pulmonary resection was administered in four cycles,
for a median of four months. Adverse effects from periop-
erative chemotherapy were assessed regularly, and agents
were reduced or discontinued as indicated if toxicity
occurred.
22
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Fig. 3. Number of lung nodules (Ps0.009).
Fig. 2. Disease-free interval (Ps0.04).
Fig. 1. 5-year overall survival curve.
The variables studied were: 1) age, 2) gender, 3) primary
site, 4) histopathologic type, 5) disease-free interval (DFI),
6) thoracic approach and type of lung resection, 7) com-
plete resection of lung metastases, and 8) re-do surgery
for oncological purposes.
Survival rates were calculated starting from the date of
surgery of pulmonary metastases, and the time to death
was modelled using the method of Kaplan–Meier. The
interrelation among survival and the factors mentioned
above was analyzed by using the log-rank and the Cox
model. In all statistical analyses, P-0.05 was considered
significant.
3. Results
In this group of twenty-two patients, the age ranged
between 13 and 82 years (median 41). Ten patients were
male (54.5%) and twelve, female (45.5%). The histologic
results of the primary tumor were: Extraskeletal Ewing’s
Sarcoma in five patients, Malignant Fibrous Histiocytoma in
four patients, Synovial Sarcoma in four patients, Fibrosar-
coma in three patients, Leyomiosarcoma and Liposarcoma
in two patients, respectively; and Alveolar Sarcoma and
Clear Cell Sarcoma in one patient, respectively. Primary
sites of the STS were lower limb in 13 cases; upper limb in
5 cases; and other locations in 4 patients (vagina, abdom-
inal wall, pelvis and spine). The DFI ranged between 5 and
84 months (median 18). The surgical thoracic approach was
thoracotomy in ninenteen patients, video assisted thoracic
surgery (VATS) in two patients and sternotomy in one
patient. The types of lung resection performed were wedge
resection in nineteen patients, lobectomy in two patients
and wedgeqlobectomy in one patient. Complete removal
of lung metastases at time of first surgery was performed
in 20 patients (90% of the cases). Re-do surgery due to
recurrent lung metastases was performed in seven patients
(31.8%); three of these patients (13.6%) went through a
third surgery for removal of recurrent lung disease. There
was no operative mortality or major morbidity, except for
one patient that required mechanical ventilation for 72 h
and another one with a persistent air-leak. Among 18
patients treated perioperatively with Ifosfamine-Adriami-
cine (A-I) regimen, four were converted to Gemcitabine
because of concerns of cardiotoxicity or poor tolerance of
A-I.
Four patients (18.2%) were alive without disease, twelve
patients (54.5%) died of disease and we lost track of the
other six patients (27.3%). We lost complete track of two
patients and we could not determine the exact date of
death of the other four. These four patients were in fact
followed for months or years and all of them were end-
stage terminally ill patients at last follow-up date. We
assumed that they passed away in the following two months
due to their severely poor clinical status. So, all statistical
calculations were based upon a total of 20 patients. The
follow-up period for this group of patients ranged from 7
to 75 months, with a median of 14 months. The median
survival was 19 months and three and five-year overall
survival rates were 47.6% and 23.1%, respectively (Fig. 1).
Univariate analysis (using the log-rank test and the Cox
model) showed that age (Ps0.17), gender (Ps0.48), pri-
mary site (Ps0.526), re-do surgery (Ps0.156) and com-
plete resection of lung metastases (Ps0.623) bear no
significant relation to survival.
On the other hand, three significant prognostic factors
(Figs. 2–4) were identified: first, DFI )1 year was related
with longer survival (Ps0.04); second, if 3 or less nodules
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New Ideas
Case Report
Protocol
Institutional
Report
Negative
Results
Nomenclature
Brief
Communication
State-of-the-art
Work in
Progress Report
Proposal for Bail-
out Procedure
Best Evidence
Topic
Follow-up
Paper
Fig. 4. Ewing vs. non-Ewing STS (Ps0.01).
had been removed the survival rate was better than if 4 or
more had been resected (Ps0.009); and third, Ewing
sarcoma patients had a poorer prognosis than those suffer-
ing non-Ewing sarcomas (Ps0.01).
4. Discussion
The series of patients analyzed show a ten-year experi-
ence in the surgical management of lung metastases of STS
at our institution. Normally, these metastases show up
when STS primary tumor cells travel through a hematoge-
nous route and get trapped in the pulmonary capillary bed.
Hence the lungs are, by far, the most frequent location for
distant metastases of these tumors.
According to the figures in our study, lung metastasecto-
mies have low morbi-mortality rates. This is basically due
to two facts: a) patients with STS lung metastases usually
have good cardiopulmonary function tests, as they do not
normally suffer from COPD or other lung or heart disorders,
as for example lung cancer patients many times do, and b)
these are conservative operations; we have to take into
account that re-do lung surgery for recurrent disease is
frequent in these patients (31.8% of patients in our series).
Various studies have demonstrated that repeated pulmo-
nary resections make it possible to control the disease for
an extended period of time w3, 7, 8x.
Long-term survival after STS lung metastasectomy has
been reported in different research works. A review of
sixty-eight patients, treated at the US National Cancer
Institute, showed a 35% three-year survival rate vs. a 28%
three-year overall survival for all patients (whether or not
having gone through lung metastasectomy) w15x, and those
who underwent incomplete resection had a median survival
of nine months. The European Organization for Research
and Treatment of Cancer–Soft Tissue and Bone Sarcoma
Group, reviewed the collective experience from 11 hospi-
tals, involving 255 patients, who underwent resection of
pulmonary metastases. They reported an overall survival
rate of 54% at three years and 38% at five years w5, 10x.
Other institutions have shown five-year survival rates rang-
ing from 21 to 25% w4, 11, 12x, very close to our own
results.
A variety of prognostic factors have been reviewed in a
number of different series. The ability to resect metastatic
disease completely is consistently the most significant
factor in determining postmetastasectomy survival. In our
study, however, complete removal of lung metastases was
not a significant prognostic factor. Most likely this was due
to the fact that two patients remained with lung disease
after surgery, one of whom we lost track of, so this small
number of patients could not be compared properly with
the group of completely resected patients. The other more
consistent predictor of survival was an extended DFI w4, 9,
13, 14x, this variable has shown statistical significance in
our study. We also examined the number of nodules resect-
ed as a prognostic factor, which in fact turned out to be a
favorable one if the number of nodules was three or lower.
This is consistent with Casson et al. w4x and Putnam et al.
w13x studies that concluded that patients with three or
fewer nodules resected at operation had longer survival
rates than patients with four or more nodules. The latter
study demonstrated that unilateral versus bilateral disease
is not a significant indicator of prognosis.
An interesting conclusion from our study, that we would
like to emphasize, is that extaskeletal Ewing’s sarcoma
turned out to be an indicator of poor prognosis. In our
series the most frequent histologic type was extra-
skeletal Ewing’s sarcoma, compared to others that in most
studies normally take this outstanding place (leyomiosar-
coma, malignant fibrous histiocytoma or synovial sarcoma)
w3, 15x. This rare histologic type had a clearly poorer
prognosis compared with the rest of sarcomas. This matter
has not been previously reported in the literature and we
think it should be borne in mind in borderline surgical cases
(e.g patients with multiple and bilateral metastases) where
a conservative treatment may be preferable to an operation
on these patients, due to their poor survival rate.
As for the four patients who were alive without disease
at the end of the period of study, three of them had gone
through re-do surgery. We did not find re-do surgery to be
a prognostic factor for survival (Ps0.156), nevertheless it
is well known that patients who can be completely re-
resected have better outcomes than those incompletely
resected w8x.
Some series have suggested that current perioperative
chemotherapy has minimal, or no impact, on survival rates
of patients undergoing pulmonary resection for metastatic
STS w2x. In our study, patients went through both periop-
erative chemotherapy and surgery, so it was not possible
for us to establish the exact role of chemotherapy by itself.
Therefore, we think that new series and medical approach-
es are needed in this setting.
We have found several limitations to our study:
a) The retrospective design;
b) The fact that chemotherapy regimens and surgical
thecniques are highly individualized based on patient
and tumor characteristics; and most important of all,
c) Results are based on a small number of patients oper-
ated in a single institution, and
d) the most important limitation: we lost track of six
patients, at some point in time, during the follow-up
period.
Prospective multi-institutional large-scale studies need to
be performed in the future to confirm our current results.
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5. Conclusion
Long-term survival is possible after resection of pulmonary
metastases from STS, although the five-year survival rate
is low (23.1%). DFI )1 year, 3 or less pulmonary metastases
and non-Ewing STS are favorable prognostic factors. Re-do
lung surgery, although not statistically significant for sur-
vival, was present in three of the four patients alive without
disease.
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