Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy
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Liposarcoma in adult limbs treated by limb-
sparing surgery and adjuvant radiotherapy
J. Issakov, Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade
V. Soyfer, liposarcoma in a limb were treated by limb-sparing surgery and post-operative
Y. Kollender, radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-
J. Bickels, free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival
I. Meller, 67%. Analysis of failure and success showed no association with the age of the patients,
O. Merimsky gender, the location of the primary tumour, the type of liposarcoma and the quality of
resection.
From Tel-Aviv Our results indicate that liposarcoma may recur even ten years after the end of definitive
Sourasky Medical therapy and may spread to unexpected sites as for soft-tissue sarcoma.
Centre, Tel-Aviv,
Israel
Liposarcoma is the most common type of soft- for distant metastases. Pleomorphic lipo-
tissue sarcoma and accounts for 25% to 30% sarcoma occurs in elderly patients, and is
of all such cases.1-5 Genetically, it is a distinct located in the limbs and the retroperitoneum.
type with fatty differentiation and a common Cytogenetically, there is a complex structural
12q amplification. Five histological variants rearrangement. This type has a high risk of
have been described, of which well-differenti- local recurrence and systemic spread. The
ated liposarcoma is seen most often (> 50% of mixed-type liposarcoma is a rare variant,
cases of liposarcoma).1-5 which shows a combined myxoid or round-cell
J. Issakov, MD, Head of Unit Well-differentiated liposarcoma usually appearance with well-differentiated and pleo-
of Musculoskeletal Pathology occurs in middle-aged or elderly patients and morphic components.1-5
Department of Pathology
V. Soyfer, MD, Radiation and arises in the limbs or retroperitoneum. Myxoid Nowadays, all liposarcomas and other types
Medical Oncologist and round-cell liposarcomas account for 30% of soft-tissue sarcoma are treated by limb-
Unit of Radiation Therapy,
Division of Oncology to 40% of all liposarcomas, are usually diag- sparing surgery, when confined to the limbs
Y. Kollender, MD, nosed in adults and rarely in children, and preceeded or followed by radiotherapy, with or
Orthopaedic Surgeon
J. Bickels, MD, Orthopaedic tends to arise intramuscularly in the limbs.1-5 without chemotherapy.6 In most cases, this has
Surgeon Genetically, there is a supernumerary ring and replaced the radical surgical approach for
I. Meller, MD, Professor,
Head of National Unit of giant marker chromosomes. The most frequent treating sarcomas of the limbs. The most
Orthopaedic Oncology genetic change is translocation t(12;16)(q13;p11). important factor which determines the feasibil-
National Unit of Orthopaedic
Oncology Liposarcomas with a round-cell component ity of limb-sparing surgery is resectability of
O. Merimsky, MD, Professor, carry a higher risk of metastasis. the tumour as assessed clinically and radio-
Head of Unit of Bone and Soft
Tissue Oncology The de-differentiated and pleomorphic types logically. Induction chemotherapy or radio-
Unit of Bone and Soft Tissue are relatively rare, each accounting for 5% of therapy may facilitate resection, and may also
Oncology
Tel-Aviv Sourasky Medical all cases.1-5 De-differentiated liposarcoma play a role in controlling the disease. Post-
Centre, 6 Weizmann Street, Tel- occurs in the second half of life and arises in operative chemotherapy is still in the experi-
Aviv 64239, Israel.
the limbs and the retroperitoneum. Geneti- mental stage, but may be used in selected
Correspondence should be sent
to Professor O. Merimsky;
cally, ring or giant chromosomes similar to cases.6 Follow-up is usually carried out for life
e-mail: those of well-differentiated liposarcoma char- and is aimed at the diagnosis of salvageable
oferm@tasmc.health.gov.il
acterise this type. Microscopically, these relapse and the detection of late local compli-
©2006 British Editorial Society tumours show areas of well-differentiated cations or the systemic effects of primary treat-
of Bone and Joint Surgery
doi:10.1302/0301-620X.88B12. liposarcoma, and non-lipogenic components. ment.
17964 $2.00 The de-differentiated component may show In this series, we report our experience of the
J Bone Joint Surg [Br] low-grade characteristics and an indolent treatment of intermediate or high-grade lipo-
2006;88-B:1647-51. behaviour or may have a high-grade pattern of sarcomas affecting adults and arising in the
Received 28 March 2006;
Accepted after revision 25 July de-differentiation, such as in malignant fibro- limbs. This is a homogeneous population
2006 histiocytoma or fibrosarcoma, and a high risk which was diagnosed by one pathologist (JI)
VOL. 88-B, No. 12, DECEMBER 2006 16471648 J. ISSAKOV, V. SOYFER, Y. KOLLENDER, J. BICKELS, I. MELLER, O. MERIMSKY
and a radiologist (not an author), treated by one team of three-weekly cycles of adriamycin and ifosfamide at the
dedicated orthopedic surgeons (YK, JB, IM) and one of two same schedule as in the pre-operative treatment only if the
sarcoma-experienced oncologists (OM, VS), with regular pathologist had reported a favourable response to chemo-
follow-up by the same team. therapy.
The surgical specimen was studied for the adequacy of
Patients and Methods resection, the percentage of necrosis within the tumour, and
Between December 1995 and March 2003, 38 consecutive the presence of vascular invasion by the tumour.
adult patients (20 men, 18 women) with a mean age of 51.1 Limb-sparing surgery was attempted in all the patients
years (18 to 84) with a liposarcoma confirmed by histo- by the same surgical team. In those who had undergone an
logical examination of a CT-guided core needle biopsy con- attempt at down-staging by pre-operative chemotherapy,
fined to a limb, were treated at our institution. The mean the operation was performed one to two weeks after the
follow-up was 67 months (9 to 123). The site of the pri- last course of chemotherapy. Pre-operative evaluation also
mary sarcoma was the thigh in 26 patients, the lower leg in included MRI of the involved limb, CT of the chest, a mul-
four, the arm in two, the popliteal fossa in two, and one tiple gated acquisition scan and a full blood count and bio-
each in the buttock, the forearm, the shoulder and the sole chemical analysis. Several patients were referred from other
of the foot. The subtype of the liposarcoma was myxoid in centres where they had undergone an excisional biopsy,
21, round-cell in 13 and pleomorphic in four. Intermediate- limited or inadequate surgery (termed as ‘first surgical
grade liposarcomas, including myxoid liposarcomas, were attempt’) for a wide local resection (second attempt) and
treated in the same way as high-grade tumours. There were adjuvant therapy. In other cases in which our first limb-
no low-grade, well-differentiated liposarcomas. The Union sparing surgery had inadequate margins, a second attempt
International Contre le Cancer (UICC)-(Tumour, nodes and with a wide local resection was carried out.
metastases (TNM) 2002) sarcoma stage was IA in one In all the cases, the pathologist (JI) reviewed the diagnos-
patient, IIA in two, and IIB in 35.7 All the patients were tic material before making a decision on the surgical and
candidates for the limb-sparing approach. In none was oncological approach. Fresh specimens from the limb-
amputation thought to be the procedure of choice. sparing procedures were obtained and examined by the
Informed consent was obtained from each patient before same pathologist and reviewed by all the other members of
any diagnostic procedure, surgical intervention, radio- the team. Macroscopic pictures of the specimen and its cut
therapy, chemotherapy or isolated limb perfusion. section were taken. The size of the liposarcoma, the surgical
Only patients with a high-grade UICC (TNM 2002) IIB margins, the presence of tumour necrosis, haemorrhage,
lesion adjacent to the neurovascular bundle or bone, with formation of a cyst, fibrosis or calcification and vascular
no serious systemic illness, were considered to be candi- invasion were studied and documented. In cases of limb-
dates for induction therapy. Those with similar lesions, sparing surgery after neo-adjuvant therapy two slices from
especially in the lower limb, who were considered poor can- the largest diameter of the tumour mass at the maximal sag-
didates for systemic induction chemotherapy because of co- ittal and tangential cross-sections were entirely embedded
morbidities, were referred for isolated limb perfusion with in paraffin and histologically examined by a mapping tech-
tumour necrosis factor alpha (TNF-α) and melphalan. This nique.10 Surgical margins of at least 1.0 cm to 1.5 cm were
method has been described in detail elsewhere.8,9 Briefly, a considered to be adequate (R0), 0.0 cm to 0.99 cm to be
bolus of 4 mg of recombinant TNF-α is injected into the marginal (Rm), and if tumour was present at the inked edge
lower limb, followed 30 minutes later by an injection of to be involved (R1). A good response to pre-operative
1.5 mg/kg body-weight of melphalan. The temperature of chemotherapy or isolated limb perfusion with TNF-α was
the perfused limb is maintained at 39˚C to 40˚C during the defined when the percentage of necrosis was more than 90.
entire procedure. Limb-sparing surgery was carried out six All the other cases were said to have a poor response.
to eight weeks after isolated limb perfusion. No systemic All the patients in our series received post-operative
adjuvant chemotherapy was given. As an alternative to iso- radiotherapy. The same team of two radiation oncologists
lated limb perfusion in patients with good mobility and (OM, VS), using a Phillips Simulator (Royal Phillips Elec-
general health, pre-operative chemotherapy was suggested. tronics, The Netherlands), carried out pre-treatment simu-
The protocol consisted of three, three-weekly identical lation. Radiotherapy was delivered through an 8 MV linear
cycles of adriamycin and ifosfamide. Adriamycin was accelerator photon beam to the target volume by two
infused at a dose of 75 mg/m2/day on day 1 over 15 minutes opposing fields, in a schedule of 1.8 Gy/fraction, five frac-
and ifosfamide at 3.0 g/m2/day on days 1 to 2 by central tions per week to a midplane dose of 63 Gy or 70 Gy in the
intravenous infusion. Mesna was given at a dose of case of marginal excision or involved margins. Field re-
3.0 g/m2/day on days 1 to 2 and half the dose on day 3. A simulation for verification was carried out in each case after
subcutaneous injection of 5 mcg/kg of granulocyte colony- 25 Gy. An initial midplane dose of 45 Gy was given to the
stimulating factor (G-CSF; Neupogen; Hoffman La Roche, tumour bed according to a pre-operative imaging study
Basel, Switzerland) was given daily, starting 24 hours after and, as marked by the surgical clips, to the surgical scar.
chemotherapy. Adjuvant chemotherapy consisted of three, Field borders were either the whole compartment, or prox-
THE JOURNAL OF BONE AND JOINT SURGERYLIPOSARCOMA IN ADULT LIMBS TREATED BY LIMB-SPARING SURGERY AND ADJUVANT RADIOTHERAPY 1649
Local recurrence-free this way, the skin received the full dose of radiotherapy. If
survival the beam had been targeting the limb and scar in a perpen-
Metastasis-free dicular way, the skin would have received a sub-optimal
100 survival
Disease-free survival dose due to the large skin-sparing effect of a 8 MV photon
Overall survival beam. In cases in which the scar had to be irradiated by a
90 perpendicular beam, a wax bolus 1 cm thick and 4 cm wide
covered the surgical scar. Interruption of radiotherapy for
80 acute skin and soft-tissue toxicity was compensated for by
the addition of radiation according to the time, dose and
Survival (%)
fractionation (TDF) values.11
70
The follow-up included a detailed history, physical
examination, measurement of the full blood count and
60 serum lactate dehydrogenase (LDH) every three months,
plain radiography of the chest every three months, and CT
50
of the chest and limb every six months, for the first two
years. Over the next three years a detailed history, physical
examination, measurement of the full blood count and
40 serum LDH, CT of the chest and MRI or CT of the limb
0 25 50 75 100 125 150 were performed every six months. Further radiological
Months after surgery studies were carried out on the basis of symptoms and clin-
ical impression.
Fig. 1a
Statistical analysis. This was performed using the two-by-
two test and Kaplan-Meier survival analysis. Overall sur-
Time to local recurrence vival was calculated from the date of positive tissue diagno-
Time to first metastasis sis until the date of death. Only the disease-specific deaths
were considered for statistical analysis.
40 Disease-free survival was calculated from the date of
definitive surgery, whether carried out primarily or after
pre-operative treatment, until the date of the first recur-
30 rence. Similarly, survival free from metastasis and from
Recurrence (%)
local recurrence were calculated from the date of definitive
20 surgery to the date of the event.
Results
10 Doxorubicin-based induction chemotherapy was adminis-
tered in 13 patients, induction isolated limb perfusion/
TNF-α in four and no induction therapy in 21. All the
0
0 25 50 75 100 125 150
patients underwent limb-sparing surgery followed by
radiotherapy. The degree of necrosis of the sarcoma after
Months after surgery induction therapy was 95% in four patients (3 chemo-
Fig. 1b therapy, 1 TNF-α), 90% to 60% in seven, and 50% or less
in four. A first attempt at resection was performed either in
Graphs showing a) the local recurrence-free, metastasis-free, disease-free
and overall survival and b) the time to local failure or to the first systemic the referral centre or, less often, in our centre. The margins
metastasis in adult patients with high-grade limb liposarcomas. of resection at the first attempt were wide and adequate in
ten patients, marginal in three, and involved in 25. The 28
patients with less than adequate margins at the first attempt
were wide in 13, marginal in 12 and involved in three at the
second attempt. The time interval between the first attempt
at surgery and the start of post-operative radiotherapy
imal and distal margins of 10 cm in non-compartmental ranged between 1.3 and 6.9 months (median 2.9). The
lesions. A coned-down field (by re-simulation) of a 5 cm mar- longer intervals stemmed mainly from the need to adminis-
gin proximally and distally received a dose up to 54 Gy, and ter adjuvant chemotherapy before radiotherapy, and less
a further re-simulated coned-down field of the tumour bed often from delayed wound healing. All the patients received
plus a 2 cm margin received a dose of up to 63 Gy or 70 Gy. radiotherapy as planned. Late effects of radiotherapy
The surgical scar and the target volume of the limb were included pain (severe in four patients, moderate in nine,
exposed, when feasible, to two opposed tangential fields. In mild in 13 and none in 12), neuromotor disturbance (severe
VOL. 88-B, No. 12, DECEMBER 20061650 J. ISSAKOV, V. SOYFER, Y. KOLLENDER, J. BICKELS, I. MELLER, O. MERIMSKY
in 3, moderate in 6, mild in 8 and none in 21), joint stiffness operative radiotherapy cannot compensate for inadequate
in six patients where the joint was adjacent to the tumour margins, in liposarcoma, according to our experience, the
bed, soft-tissue damage (stony-hard induration in 6, mod- situation was different. Radiation therapy achieved good
erate stiffness in 7, mild in 12 and none in 13), chronic local control even in patients with positive margins.
lymphoedema in eight, radiation-related fracture in two, The European Society of Medical Oncology (ESMO)
arterial insufficiency in one with known peripheral vascular minimum clinical recommendations for diagnosis, treat-
disease, chronic ulceration requiring treatment with a free ment and follow-up of soft-tissue sarcoma have recently
flap in one and severe infection necessitating amputation in been published.15 The issue of follow-up is very clear:
one. “Early detection of recurrence might influence the possibil-
Local recurrence was observed in six patients and meta- ity of a curative treatment. The patient should be followed
static disease in ten. The sites of the first recurrence were the every three months with history and physical examination.
lung in three, soft tissues of the neck in one, the thyroid in MRI of the site of resection of the primary tumour is pro-
one, the retroperitoneum in two, the heart in one, the spine posed twice a year for the first two to three years and then
in one and the soft tissue and liver in one. The ten-year local once a year. For patients with high-grade tumours, a chest
recurrence-free survival was 83%, the ten-year metastasis- radiograph is recommended every three to four months in
free survival 61%, the ten-year disease-free survival 51% the first two to three years, twice a year up to the fifth year,
and the ten-year outcome survival 67%. The median values and once a year thereafter”.15 The importance of the fol-
of these parameters have not been reached as yet (Fig. 1). low-up was well described in the International Sarcoma
Analysis of failure and success in terms of the local and Meeting in Stuttgart.16 It was claimed that follow-up in
distant recurrence-free survival, disease-free survival and patients with soft-tissue sarcoma is essential for several rea-
overall survival showed no association with the age of the sons. The most important aim of a thorough follow-up is
patient (at cut-off points of 40, 50 and 60 years of age), the early diagnosis of treatable, resectable and potentially
gender, the location of the primary tumour (upper vs lower curable recurrences, either localised or systemic. Local
limb), the type of liposarcoma (myxoid liposarcoma vs recurrence after limb-sparing surgery, or stump recurrence
non-myxoid liposarcoma) and the quality of resection (pos- after amputation, may be excised and sometimes re-irradi-
itive or marginal resection vs wide margins). ated, by teletherapy or by brachtherapy. Pulmonary meta-
stases, for instance, especially when single, can be resected,
Discussion and the patient can re-achieve the status of no evidence of
The results achieved in our series are comparable with disease. Brain metastases, although infrequent in soft-tissue
those reported in the literature for heterogeneous popula- sarcoma, may be resected and irradiated. The second aim of
tions of soft-tissue sarcoma and homogeneous populations follow-up is the detection and treatment of therapy-related
of specific histological types such as malignant fibrohistio- late complications such as lymphoedema, pain, loss of
cytoma treated by limb-sparing surgery and radio- muscular function because of fibrosis, chronic wounds, vas-
therapy.12-14 We believe that this is the first report of a cular problems, weakening of bone and fractures. These
homogeneous series of limb liposarcoma treated similarly events are not uncommon and have considerable influence
by a single centre. on the patients’ quality of life.
Our results point to several important issues of local Three important points have not been referred to in the
recurrence, systemic recurrence, disease-free survival and ESMO guidelines. The first is the difference in approach to
overall survival. The period of risk for local recurrence is the various types of soft-tissue sarcoma. All histological
the first three years after definitive surgery. Thereafter, there types of soft-tissue sarcoma of the limb are treated in the
were no further local relapses. Systemic recurrence may same way by surgery, radiotherapy, with or without neo-
occur even ten years after definitive surgery and after radio- adjuvant or adjuvant chemotherapy. There is no difference
therapy. The disease-free survival curve reflects the summa- in the recommendations for follow-up. Liposarcomas and
tion of local and systemic spread. The overall survival curve malignant fibrohistiocytoma, or fibrosarcomas, are fol-
seems to be more optimistic than the disease-free survival lowed by the same protocol of survey of the primary site
curve because several events of systemic recurrence may be and lung. According to our experience, liposarcoma may
treated and even cured. Surprisingly, we could find no link recur locally and in the lungs, but also in the bones, other
between the patients’ characteristics, the type of tumour uncommon sites such as the lymph nodes, soft tissues,
and the quality of resection and the outcome in terms of the spine, retroperitoneum, and even in the thyroid. The unpre-
local recurrence-free survival, metastasis-free survival, dis- dictable spread of liposarcoma seems to be a characteristic
ease-free survival and overall survival. The most important feature of this tumour, in contradiction to malignant fibro-
finding was the lack of influence of the margins of resection histiocytoma,17 which tends to recur during the first two
on the local control of the disease. This observation empha- years. A whole-body CT scan may reveal new sites of
sises the importance and efficacy of the radiotherapy. While spread, but practically, a repeated routine whole-body scan
negative margins are generally required in soft-tissue sar- may not be feasible. Clinical awareness of this phenomenon
coma in order to have satisfactory local control and post- should be kept in mind.
THE JOURNAL OF BONE AND JOINT SURGERYLIPOSARCOMA IN ADULT LIMBS TREATED BY LIMB-SPARING SURGERY AND ADJUVANT RADIOTHERAPY 1651
The second issue is the duration of follow-up. Follow-up References
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